Controlled release preparation

ABSTRACT

A controlled release preparation wherein the release of active ingredient is controlled, which releases an active ingredient for an extended period of time by staying or slowly migrating in the gastrointestinal tract, is provided by means such as capsulating a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. Said tablet, granule or fine granule has a release-controlled coating-layer formed on a core particle containing an active ingredient.

This application is a continuation of U.S. Ser. No. 10/531,069 filedApr. 11, 2005, now U.S. Pat. No. 7,790,755 which is a U.S. NationalStage application of International No. PCT/JP2003/013155, filed Oct. 15,2003, which applications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a controlled release preparation, inparticular a capsule comprising a tablet, granule or fine granulewherein the release of active ingredient is controlled and a gel-formingpolymer which delays the migration speed in the gastrointestinal tract.

BACKGROUND ART

An oral formulation is a dosage form which is used most frequently amongpharmaceutical agents. Lots of preparations for oral administrationwherein the drug efficacy thereof is sustained with the administrationof once or twice a day have been developed from the viewpoint ofimproving QOL in these years. The compound having a kinetics ofsustained drug efficacy with the administration of once or twice a dayis tried to synthesize in the synthetic stage of compound itself, whilequite a lot of attempts to modify the kinetics are made with designingcontrolled release preparation by contriving formulation. As the dosageform of oral controlled release preparation, various release-controlledsystems such as a release control by a release-controlled coating-layeror a diffusion control of compound by a matrix, a release control ofcompound by erosion of matrix (base material), a pH-dependent releasecontrol of compound and a time-dependent release control wherein thecompound is released after a certain lag time, are developed andapplied. It is considered that a further extension of sustainabilitybecomes possible by combining the above-mentioned release-controlledsystem with a control of migration speed in the gastrointestinal tract.

The preparation containing a medicament having an acid-labile propertyas an active ingredient such as a benzimidazole compound having a protonpump inhibitor (hereinafter sometimes referred to as PPI) action needsto be enteric-coated. That is, a composition containing a benzimidazolecompound having a proton pump inhibitor action is needed to disintegraterapidly in the small intestine, so the composition is preferred toformulate into a granule or fine granule which has a broader surfacearea than a tablet and is easy to disintegrate or dissolve rapidly. Inthe case of a tablet, it is desirable to reduce the size of tablet (forexample, see JP-A 62-277322).

After administered orally, the tablet, granule or fine granule migratesthrough gastrointestinal tract with releasing an active ingredient tostomach, duodenum, jejunum, ileum and colon sequentially. And in themeantime, the active ingredient is absorbed at the each absorption site.A controlled release preparation is designed to control the absorptionby delaying the release of active ingredient in some way. It isconsidered that a further extension of sustainability becomes possibleby combining a release-controlled system with a function to control themigration speed in gastrointestinal tract such as adherability,floatability etc. These prior arts are disclosed in WO 01/89483, JP-A2001-526213, U.S. Pat. No. 6,274,173, U.S. Pat. No. 6,093,734, U.S. Pat.No. 4,045,563, U.S. Pat. No. 4,686,230, U.S. Pat. No. 4,873,337, U.S.Pat. No. 4,965,269, U.S. Pat. No. 5,021,433 and the like.

DISCLOSURE OF INVENTION Object of the Invention

An object of the present invention is to provide a controlled releasepreparation wherein the release of active ingredient of drug iscontrolled, which releases an active ingredient for an extended periodof time with staying or slowly migrating in the gastrointestinal tract.

SUMMARY OF THE INVENTION

That is, the present invention provides:

(1) A capsule comprising a tablet, granule or fine granule wherein therelease of active ingredient is controlled and a gel-forming polymer;

(2) The capsule according to the above-mentioned (1), wherein therelease of active ingredient is controlled by a release-controlledcoating-layer formed on a core particle containing an active ingredient;

(3) The capsule according to the above-mentioned (2), wherein therelease-controlled coating-layer contains a pH-dependently solublepolymer;

(4) The capsule according to the above-mentioned (2), wherein therelease-controlled coating-layer is a diffusion-controlled layer;

(5) The capsule according to the above-mentioned (1), wherein therelease of active ingredient is controlled by dispersing an activeingredient into a release-controlled matrix composing tablet, granule orfine granule;

(6) The capsule according to the above-mentioned (3) or (4), wherein thetablet, granule or fine granule in which the release of activeingredient is controlled has a disintegrant layer containingdisintegrant formed on the core particle containing an active ingredientand a release-controlled coating-layer formed on said disintegrantlayer, and the release of active ingredient is initiated after a certainlag time;

(7) The capsule according to any one of the above-mentioned (3) to (6),wherein the tablet, granule or fine granule in which the release ofactive ingredient is controlled is coated with a gel-forming polymer;

(8) The capsule according to the above-mentioned (7) which furthercontains a gel-forming polymer;

(9) The capsule according to any one of the above-mentioned (1) to (7),which comprises two kinds of tablet, granule or fine granule havingdifferent release properties of active ingredient;

(10) The capsule according to the above-mentioned (9), which comprises atablet, granule or fine granule having an enteric coat that releases anactive ingredient at the pH of about 5.5 and a tablet, granule or finegranule having a release-controlled coating-layer that releases anactive ingredient at the pH of about 6.0 or above;

(11) The capsule according to the above-mentioned (1), (7) or (8),wherein the gel-forming polymer is a polymer whose viscosity of 5%aqueous solution is about 3,000 mPa·s or more at 25° C.;

(12) The capsule according to the above-mentioned (1), (7) or (8),wherein the gel-forming polymer is a polymer having molecular weight of400,000 to 10,000,000;

(13) The capsule according to any one of the above-mentioned (2) to (4)or (6), wherein the release-controlled coating-layer is a layercontaining one or more kinds of polymeric substances selected from thegroup consisting of hydroxypropylmethyl cellulose phthalate, celluloseacetate phthalate, carboxymethylethyl cellulose, methylmethacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylatecopolymer, ethyl acrylate-methyl methacrylate-trimethylammoniumethylmethacrylate chloride copolymer, methyl methacrylate-ethyl acrylatecopolymer, methacrylic acid-methyl acrylate-methyl methacrylatecopolymer, hydroxypropyl cellulose acetate succinate and polyvinylacetate phthalate;

(14) The capsule according to the above-mentioned (13), wherein therelease-controlled coating-layer is comprised of 2 or more kinds oflayers;

(15) The capsule according to the above-mentioned (1), wherein therelease-controlled granule or fine granule has a particle size of about100-1,500 μm;

(16) The capsule according to the above-mentioned (1), wherein theactive ingredient is a proton pump inhibitor (PPI);

(17) The capsule according to (16), wherein the PPI is an imidazolecompound represented by the formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof;

(18) The capsule according to the above-mentioned (17), wherein theimidazole compound is lansoprazole;

(19) The capsule according to the above-mentioned (17), wherein PPI isan optically active R-isomer of lansoprazole;

(20) The capsule according to any one of the above-mentioned (1), (7) or(8), wherein the gel-forming polymer is one or more kinds of substancesselected from the group consisting of polyethylene oxide (PEO, molecularweight: 400,000-10,000,000), hydroxypropylmethyl cellulose (HPMC),carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC),hydroxyethyl cellulose and carboxyvinyl polymer;

(21) The capsule according to any one of the above-mentioned (1), (7) or(8), wherein the gel-forming polymer is polyethylene oxide (molecularweight: 400,000-10,000,000);

(22) The capsule according to the above-mentioned (1) or (8), whereinthe gel-forming polymer is added as a powder, fine granule or granule;

(23) The capsule according to the above-mentioned (3), wherein thepH-dependently soluble polymer is methyl methacrylate-methacrylic acidcopolymer;

(24) A tablet, granule or fine granule wherein the release of activeingredient is controlled, said tablet, granule or fine granulecomprising a core particle containing an imidazole compound representedby the formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as an active ingredient, anda pH-dependently soluble release-controlled coating-layer whichcomprises one kind of polymeric substance or a mixture of two or morekinds of polymeric substances having different release propertiesselected from the group consisting of hydroxypropylmethyl cellulosephthalate, cellulose acetate phthalate, carboxymethylethyl cellulose,methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethylacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylatecopolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetatephthalate and shellac, and said polymeric substance is soluble in the pHrange of 6.0 to 7.5;

(25) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the pH-dependently solublerelease-controlled coating-layer is formed on an intermediate layerwhich is formed on a core particle;

(26) The capsule comprising the tablet, granule or fine granuleaccording to the above-mentioned (24);

(27) The capsule comprising the tablet, granule or fine granuleaccording to the above-mentioned (24) and an enteric-coated tablet,granule or fine granule containing a compound represented by the formula(I′);

(28) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the active ingredient is lansoprazole;

(29) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the active ingredient is an opticallyactive R-isomer of lansoprazole;

(30) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the active ingredient is an opticallyactive S-isomer of lansoprazole;

(31) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the active ingredient is a derivative oflansoprazole;

(32) The tablet, granule or fine granule according to theabove-mentioned (24), wherein the active ingredient is a derivative ofoptically active R-isomer of lansoprazole;

(33) The tablet, granule or fine granule according to any one of theabove-mentioned (24), (25) or (28) to (32), comprising having an entericcoat on the core particle containing an active ingredient, adisintegrant layer containing disintegrant on said enteric coat and arelease-controlled coating-layer on said disintegrant layer;

(34) The tablet, granule or fine granule according to any one of theabove-mentioned (28) to (33), which is coated with a gel-formingpolymer;

(35) An extended release capsule comprising the tablet, granule or finegranule according to any one of the above-mentioned (28) to (32) and agel-forming polymer;

(36) A tablet, granule or fine granule according to the above-mentioned(24) wherein the release of active ingredient is controlled by two ormore kinds of release-controlled coating-layers, and the outermostrelease-controlled coating-layer is soluble at higher pH than the innerrelease-controlled coating-layer;

(37) The tablet, granule or fine granule according to theabove-mentioned (36), wherein the inner release-controlled coating-layeris soluble in the pH range of 6.0-7.0 and the outermostrelease-controlled coating-layer is soluble at the pH of 7.0 or above;

(38) The tablet, granule or fine granule according to theabove-mentioned (36), wherein the inner release-controlled coating-layeris soluble in the pH range of 6.5-7.0 and the outermostrelease-controlled coating-layer is soluble at the pH of 7.0 or above;

(39) The tablet, granule or fine granule according to theabove-mentioned (36), wherein the thickness of the outermostrelease-controlled coating-layer is 100 μm or less;

(40) The granule or fine granule according to the above-mentioned (36),wherein the release-controlled granule or fine granule has a particlesize of about 100-1,500 μm;

(41) A capsule comprising

(i) a tablet, granule or fine granule in which the release of activeingredient is controlled; said tablet, granule or fine granule comprises

a core particle containing an imidazole compound represented by theformula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as an active ingredient, anda pH-dependently soluble release-controlled coating-layer whichcomprises one kind of polymeric substance or a mixture of two or morekinds of polymeric substances having different release propertiesselected from the group consisting of hydroxypropylmethyl cellulosephthalate, cellulose acetate phthalate, carboxymethylethyl cellulose,methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethylacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylatecopolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetatephthalate and shellac; said polymeric substance is soluble in the pHrange of 6.0 to 7.5, and(ii) a tablet, granule or fine granule comprising a core particlecontaining an active ingredient and enteric coatwhich is dissolved,thereby an active ingredient being released in the pH range of no lessthan 5.0, nor more than 6.0;

(42) The capsule according to the above-mentioned (41), wherein thepH-dependently soluble release-controlled coating-layer is formed on anintermediate layer which is formed on the core particle containing anactive ingredient;

(43) The capsule according to the above-mentioned (41), wherein theactive ingredient is lansoprazole;

(44) The capsule according to the above-mentioned (41), wherein theactive ingredient is an optically active R-isomer of lansoprazole;

(45) The capsule according to the above-mentioned (41), wherein theactive ingredient is an optically active S-isomer of lansoprazole;

(46) The capsule according to the above-mentioned (41), wherein the coreparticle containing an active ingredient contains a stabilizer of basicinorganic salt;

(47) The capsule according to the above-mentioned (41), wherein thepH-dependently soluble release-controlled coating-layer of the tablet,granule or fine granule in which the release of an active ingredient iscontrolled is a layer soluble in the pH range of no less than 6.5, normore than 7.0;

(48) The capsule according to the above-mentioned (47), wherein thepH-dependently soluble release-controlled coating-layer contains amixture of two or more kinds of methyl methacrylate-methacrylic acidcopolymers having different release properties; and

(49) The capsule according to the above-mentioned (41), which furthercontains a gel-forming polymer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition containinga tablet, granule or fine granule wherein the release of activeingredients is controlled, or a pharmaceutical composition containingthese tablet, granule or fine granule and a gel-forming polymer whichdelays digestive tract migration speed. The pharmaceutical compositionof the present invention may be these tablet, granule or fine granuleitself, or a form of a mixture of a tablet, granule or fine granule anda gel-forming polymer, or a capsule filled in capsule, but a capsule ispreferred in particular. It has been cleared that the persistence ofblood levels after oral administration is remarkably prolonged by thesecombinations.

The release control of active ingredient in “a tablet, granule or finegranule wherein the release of active ingredient is controlled” of thepresent invention is performed by coating the active ingredient in atablet, granule or fine granule with a layer controlling the release ofactive ingredient, or by dispersing the active ingredient inrelease-controlled matrices. Further, the “tablet, granule or finegranule wherein the release of active ingredient is controlled” of thepresent invention include also a tablet, granule or fine granule whichis coated with a usual enteric coat which is dissolved at a pH of about5.5, and tablets containing these granules or fine granules.

On the other hand, when the “release-controlled coating-layer” ismentioned in the present specification, it indicates a coating-layerhaving a function of further delaying or extending the release of activeingredient, such as a pH-dependently soluble layer which is dissolved ata higher pH region than a usual enteric coating which is dissolved at apH of about 5.5, and a diffusion-controlled layer whose layer itself isnot dissolved and which releases an active ingredient through poreswhich are formed in the layer. It does not include a usual enteric coatand layer which is dissolved at a pH of about 5.5, rapidly dissolved inthe intestinal juice and release an active ingredient. Further, the pHmentioned here means a pH of the Mcilvaine solution or Clark-Lubssolution. Hereinafter, the pH of a pH-dependently soluble layer meansthe pH of these solutions.

The coating-layer of the “release-controlled coating-layer” includescoating layers in a film form and those having larger thickness. Also,the coating-layer includes not only a coating-layer which entirely coatsthe inner core or layer but also the coating layers in which a part ofthe inner core or layer is not covered but most of the inner core orlayer is coated (coating-layer which covers at least about 80% or moreof the surface of the inner core or layer, and preferably covers thesurface entirely).

The absorption from the digestive tract of the active ingredient fromthe pharmaceutical composition of the present invention is controlled bytwo kind of systems utilizing (1) a release control of active ingredientby a controlled release tablet, granule or fine granule and (2)retentive prolongation in the digestive tract of a tablet, granule orfine granule by a gel-forming polymer, or their combinations. Among thepharmaceutical composition of the present invention, the compositioncontaining a gel-forming polymer forms adhesive gels by rapidlyabsorbing water by the gel-forming polymer in the digestive tract whenorally administrated, and the tablet, granule or fine granule isretained on the surface of gels or in the gels to be gradually migratedthrough the digestive tract. The release of active ingredient iscontrolled in the meanwhile, the active ingredient is releasedcontinuously or in a pulsatile manner from the tablet, granule or finegranule by a controlled system, and as a result, the incidences ofprolonged absorption and drug efficacy are attained.

The above-mentioned system enabling the persistence of therapeuticeffective levels by controlling the release over a long time hasadvantages of therapeutic effectiveness at a low dose and reduction ofside effects caused by initial rise of blood level and the like, as wellas the reduction of administration times.

The gel-forming polymer may be a polymer which rapidly forms highlyviscous gels by contacting with water and prolongs the retention time inthe digestive tract. Such gel-forming polymer is preferably a polymerhaving a viscosity of about 3000 mPa·s or more for 5% aqueous solutionat 25° C. Further, the gel-forming polymer is preferably a polymerusually having a molecular weight of about 400000 to 10000000 ingeneral. As the gel-forming polymer, powder, granular or fine granularpolymer is preferable for producing formulations. The gel-formingpolymer includes a polyethylene oxide (PEO, for example, Polyox WSR 303(molecular weight: 7000000), Polyox WSR Coagulant (molecular weight:5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSR N-60K(molecular weight: 2000000), and Polyox WSR 205 (molecular weight:600000); manufactured by Dow Chemical Co., Ltd.), hydroxypropylmethylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, and Metlose90SH30000; manufactured by Shin-Etsu Chemical Co., Ltd.),carboxymethylcellulose (CMC-Na, Sanlose F-1000MC), hydroxypropylcellulose (HPC, for example, HPC-H, manufactured by Nippon Soda Co.,Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (HIVISWAKO (R)103, 104 and 105 manufactured by Wako Pure Chemical Industries Ltd.;CARBOPOL 943 manufactured by Goodrich Co., Ltd.), chitosan, sodiumalginate, pectin and the like. These may be used alone or as a mixtureof at least 2 or more of powders by mixing at an appropriate proportion.In particular, PEO, HPMC, HPC, CMC-Na, carboxyvinyl polymer and the likeare preferably used as a gel-forming polymer.

One preferable form of a tablet, granule or fine granule wherein therelease of active ingredient is controlled includes a tablet, granule orfine granule wherein a core particle containing at least one activeingredient is coated with a release-controlled coating-layer and atablet containing these granules or fine granules. In order to preparesuch core-possessing tablet, granule or fine granule, as a core particlecan be used the tablet, granule or fine granule wherein an activeingredient is coated on a core which is an inactive carrier such asNONPAREIL (NONPAREIL-101 (particle diameter: 850-710, 710-500, and500-355), NONPAREIL-103 (particle diameter: 850-710, 710-500, and500-355), NONPAREIL-105 (particle diameter: 710-500, 500-355 and300-180); manufactured by Freund Industrial Co., Ltd.) and Celphere(CP-507 (particle diameter: 500-710), and CP-305 (particle diameter:300-500); manufactured by Asahi Kasei Corporation); or the tabletprepared by using these granules or fine granules; or the particleobtained by granulation using an active ingredient and an excipientusually used for formulation. For example, they can be produced by themethod disclosed in JP-A 63-301816. For example, when a core particle isprepared by coating an active ingredient on a core of an inactivecarrier, core particles containing an active ingredient can be producedby wet granulation, using, for example, a centrifugal fluid-bedgranulator (CF-mini, CF-360, manufactured by Freund Industrial Co.,Ltd.) or a centrifugal fluidized coating granulator (POWREX MP-10), orthe like. Further, coating may be carried out by dusting an activeingredient while adding a solution containing a binder and the like onthe core of an inactive carrier with spray and the like. The productionapparatuses are not limited and for example, it is preferable in thelatter coating to produce them using a centrifugal fluid-bed granulatorand the like. An active ingredient may be coated at two steps bycarrying out the coating using the above-mentioned two apparatuses incombination. When an inactive carrier core is not used, a core particlecan be produced by granulating excipient such as lactose, white sugar,mannitol, corn starch and crystalline cellulose and an activeingredient, using binders such as hydroxypropyl methylcellulose,hydroxypropyl cellulose, methyl cellulose, a polyvinyl alcohol,Macrogol, Pullronic F68, gum arabic, gelatin and starch, if necessary,adding disintegrants such as sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, sodium cross carboxymethyl cellulose(Ac-Di-Sol, manufactured by FMC International Co., Ltd.), polyvinylpyrrolidone and low substituted hydroxypropyl cellulose, with a stirringgranulator, a wet extruding granulator, a fluidized bed granulator andthe like.

Particles having desired sizes can be obtained by sieving the granulesor fine granules obtained. The core particle may be prepared by drygranulation with a roller compactor and the like. Particles having aparticle size of 50 μm to 5 mm, preferably 100 μm to 3 mm and morepreferably 100 μm to 2 mm are used.

The active ingredient-containing core particle thus obtained may befurther coated to provide an intermediate coating layer, and theparticle may be used as a core particle. It is preferable from theviewpoint of improving the stability of drugs that the intermediatecoating layer is provided to intercept the direct contact of activeingredient-containing core particle with the release-controlledcoating-layer when the active ingredient is an unstable drug against anacid, such as PPI and the like, etc. The intermediate coating layer maybe formed by a plural number of layers.

The coating materials for the intermediate coating layer include thoseobtained by appropriately compounding polymeric materials such as lowsubstituted hydroxypropyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose (for example, TC-5 and the like),polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose andhydroxyethyl methylcellulose with saccharides such as sucrose [purifiedsucrose (pulverized (powdered sugar), not pulverized) and the like],starch saccharide such as corn starch, lactose, sugar alcohol(D-mannitol, erythritol and the like). Excipients (for example, maskingagents (titanium oxide and the like) and antistatic agents (titaniumoxide, talc and the like) may be suitably added to the intermediatecoating layer for the preparations mentioned below, if necessary.

The coating amount of the intermediate coating layer is usually about0.02 part by weight to about 1.5 parts by weight based on 1 part byweight of granules containing an active ingredient, and preferably about0.05 part by weight to about 1 part by weight. The coating can becarried out by conventional methods. For example, preferably, thecomponents of the intermediate coating layer are diluted with purifiedwater and sprayed to coat in liquid form. Then, it is preferable tocarry out the coating while spraying a binder such as hydroxypropylcellulose.

As the controlled release tablet, granule or fine granule contained inthe pharmaceutical composition of the present invention, it ispreferable to coat the above-mentioned core particle with a coatingmaterial which is pH-dependently dissolved/eluted to control therelease, and to prepare the tablet, granule or fine granule having arelease-controlled coating-layer, or the tablet containing thesecontrolled release granules or fine granules. Herein, the“pH-dependently” means that the coating material is dissolved/elutedunder the circumstances of more than a certain pH value to release anactive ingredient. A usual enteric coat is eluted at a pH of about 5.5to initiate the release of drug, while the coating material of thepresent invention is preferably a substance which is dissolved at ahigher pH (preferably a pH of 6.0 or above and 7.5 or below, and morepreferably a pH of 6.5 or above and below 7.2) and controls morefavorably the release of drug in the stomach.

As a coating material for controlling pH-dependently the release ofmedical active ingredient, polymers such as hydroxypropylmethylcellulose phthalate (HP-55, HP-50 manufactured by Shin-EtsuChemical Co., Ltd.), cellulose acetate phthalate, carboxymethylethylcellulose (CMEC manufactured by Freund Industrial Co., Ltd.),methyl methacrylate-methacrylic acid copolymer (Eudragit L100(methacrylic acid copolymer L) or Eudragit 5100 (methacrylic acidcopolymer S); manufactured by Rohm Co.), methacrylic acid-ethyl acrylatecopolymer (Eudragit L100-55 (dried methacrylic acid copolymer LD) orEudragit L30D-55 (methacrylic acid copolymer LD); manufactured by RohmCo.), methacrylic acid-methyl acrylate-methyl methacrylate copolymer(Eudragit FS30D manufactured by Rohm Co.), hydroxypropyl celluloseacetate succinate (HPMCAS manufactured by Shin-Etsu Chemical Co., Ltd.),polyvinyl acetate phthalate and shellac are used. The tablet, granule orfine granule may be those having two or more kinds of release-controlledcoating-layers which have different release properties of activeingredient. The polymer as the above-mentioned coating material may beused alone or at least 2 or more kinds of the polymers may be used tocoat in combination, or at least 2 or more kinds of the polymers may becoated sequentially to prepare multi-layers. It is desirable that thecoating material is used alone or, if necessary, in combination so thatthe polymer is dissolved preferably at a pH of 6.0 or above, morepreferably at a pH of 6.5 or above, and further more preferably at a pHof 6.75 or above. Further, more desirably, a polymer soluble at a pH of6.0 or above and a polymer soluble at a pH of 7.0 or above are used incombination, and furthermore desirably, a polymer soluble at a pH of 6.0or above and a polymer soluble at a pH of 7.0 or above are used incombination at a ratio of 1:0.5 to 1:5.

Further, plasticizers such as a polyethylene glycol, dibutyl sebacate,diethyl phthalate, triacetin and triethyl citrate, stabilizers and thelike may be used for coating, if necessary. The amount of coatingmaterial is 5% to 200% based on the core particle, preferably 20% to100% and more preferably 30% to 60%. The rate of elution of activeingredient from the active ingredient release-controlled tablet, granuleor fine granule thus obtained is desirably 10% or less for 5 hours in asolution of pH 6.0, and 5% or less for one hour and 60% or more for 8hours in a solution of pH 6.8.

The controlled release tablet, granule or fine granule (hereinafter,sometimes referred to simply as a controlled release granule) may be atablet, granule or fine granule wherein a material which becomes viscousby contact with water, such as polyethylene oxide (PEO, for example,Polyox WSR 303 (molecular weight: 7000000), Polyox WSR Coagulant(molecular weight: 5000000), Polyox WSR 301 (molecular weight: 4000000),Polyox WSR N-60K (molecular weight: 2000000), and Polyox WSR 205(molecular weight: 600000); manufactured by Dow Chemical Co., Ltd.),hydroxypropyl methylcellulose (HPMC, Metlose 90SH10000, Metlose90SH50000, Metlose 90SH30000; manufactured by Shin-Etsu Chemical Co.,Ltd.), carboxymethyl cellulose (CMC-Na, Sanlose F-1000MC), hydroxypropylcellulose (HPC, for example, HPC-H manufactured by Nippon Soda Co.,Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (HIVISWAKO (R)103, 104, 105: manufactured by Wako Pure Chemical Industries Ltd.;CARBOPOL 943 manufactured by Goodrich Co., Ltd.), chitosan, sodiumalginate and pectin, is coated on the active ingredientrelease-controlled tablet, granule or fine granule thus obtained.

The controlled release granule may be a form in which the core particlecontaining an active ingredient is coated with a diffusion-controlledlayer having an action of controlling the release of active ingredientby diffusion. The materials for these diffusion-controlled layer includeethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylatechloride copolymer (Eudragit RS (aminoalkyl methacrylate copolymer RS)or Eudragit RL (aminoalkyl methacrylate copolymer RL); manufactured byRohm Co.), methyl methacrylate-ethyl acrylate copolymer (Eudragit NE30Dmanufactured by Rohm Co.), ethyl cellulose and the like. Further, thesematerials for layer may be mixed at an appropriate ratio, and can beused by mixing with hydrophilic pore forming substances such as HPMC,HPC, carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitoland organic acid at a fixed ratio.

Further, in order to prepare the tablet, granule or fine granule whereinthe release of active ingredient is controlled to initiate after a fixedlag time, a disintegrant layer is provided between the core particlecontaining an active ingredient and the release-controlled coating-layerby coating a swelling substance such as a disintegrant previously beforecoating the above-mentioned diffusion-controlled layer. For example,preferably, a swelling substance such as cross carmelose sodium(Ac-Di-Sol, manufactured by FMC International Co.), carmelose calcium(ECG 505, manufactured by Gotoku Chemicals Co.), CROSSPOVIDON (ISP Inc.)and low substituted hydroxypropyl cellulose (L-HPC manufactured byShin-Etsu Chemical Co., Ltd.) is primarily coated on a core particle,and then the resulting coated particle is secondarily coated with adiffusion-controlled layer which is prepared by mixing at a fixed ratioone or more kinds of polymers selected from ethyl acrylate-methylmethacrylate-trimethylammoniumethyl methacrylate chloride copolymer(Eudragit RS or Eudragit RL; manufactured by Rohm Co.), methylmethacrylate-ethyl acrylate copolymer (Eudragit NE30D manufactured byRohm Co.), ethyl cellulose and the like; with hydrophilic pore formingsubstances such as HPMC, HPC, carboxyvinyl polymer, polyethylene glycol6000, lactose, mannitol and an organic acid. The secondary coatingmaterial may be enteric polymers which release pH-dependently an activeingredient, such as hydroxypropyl methylcellulose phthalate (HP-55,HP-50; manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetatephthalate, carboxymethyl ethylcellulose (CMEC; manufactured by FreundIndustrial Co., Ltd.), methyl methacrylate-methacrylic acid copolymer(Eudragit L100 (methacrylic acid copolymer L) or Eudragit 5100(methacrylic acid copolymer S); manufactured by Rohm Co.), methacrylicacid-ethyl acrylate copolymer (Eudragit L100-55 (dried methacrylic acidcopolymer LD) or Eudragit L30D-55 (methacrylic acid copolymer LD);manufactured by Rohm Co.), methacrylic acid-methyl acrylate-methylmethacrylate copolymer (Eudragit FS30D; manufactured by Rohm Co.),hydroxypropyl cellulose acetate succinate (HPMCAS; manufactured byShin-Etsu Chemical Co., Ltd.), polyvinyl acetate and shellac. The amountof coating material is 1% to 200% based on the core particle, preferably20% to 100% and more preferably 30% to 60%.

Plasticizers such as polyethylene glycol, dibutyl sebacate, diethylphthalate, triacetin and triethyl citrate, stabilizers and the like maybe used for coating, if necessary. The controlled release tablet,granule or fine granule may be a tablet, granule or fine granule whereina material which becomes viscous by contact with water, such aspolyethylene oxide (PEO, for example, Polyox WSR 303 (molecular weight:7000000), Polyox WSR Coagulant (molecular weight: 5000000), Polyox WSR301 (molecular weight: 4000000), Polyox WSR N-60K (molecular weight:2000000), and Polyox WSR 205 (molecular weight: 600000); manufactured byDow Chemical Co., Ltd.), hydroxypropyl methylcellulose (HPMC, Metlose90SH10000, Metlose 90SH50000, Metlose 90SH30000; manufactured byShin-Etsu Chemical Co., Ltd.), carboxymethyl cellulose (CMC-Na, SanloseF-1000MC), hydroxypropyl cellulose (HPC, for example, HPC-H manufacturedby Nippon Soda Co., Ltd.), hydroxyethyl cellulose (HEC), carboxyvinylpolymer (HIVISWAKO (R) 103, 104, 105: manufactured by Wako Pure ChemicalIndustries Ltd.; CARBOPOL 943 manufactured by Goodrich Co., Ltd.),chitosan, sodium alginate and pectin, is coated on the active ingredientrelease-controlled tablet, granule or fine granule thus obtained.

In the tablet, granule or fine granule having 2 or more kinds ofrelease-controlled coating-layers having different release properties ofactive ingredient, a layer containing an active ingredient may be set upbetween said release-controlled coating-layers. A form of thesemulti-layer structure containing an active ingredient betweenrelease-controlled coating-layers includes a tablet, granule or finegranule which is prepared by coating an active ingredient on the tablet,granule or fine granule wherein the release of active ingredient iscontrolled by the release-controlled coating-layer of the presentinvention, followed by further coating with the release-controlledcoating-layer of the present invention.

Another form of the tablet, granule or fine granule wherein the releaseof at least one of the active ingredients is controlled may be a tablet,granule or fine granule in which the active ingredients are dispersed ina release-controlled matrix. These controlled release tablet, granule orfine granule can be produced by homogeneously dispersing the activeingredients into hydrophobic carriers such as waxes such as hardenedcastor oil, hardened rape seed oil, stearic acid and stearyl alcohol,and polyglycerin fatty acid ester. The matrix is a composition in whichthe active ingredients are homogeneously dispersed in a carrier. Ifnecessary, excipients such as lactose, mannitol, corn starch andcrystalline cellulose which are usually used for preparation of a drugmay be dispersed with the active ingredients. Further, powders ofpolyoxyethylene oxide, cross-linked acrylic acid polymer (HIVISWAKO (R)103, 104 and 105, CARBOPOL), HPMC, HPC, chitosan and the like which formviscous gels by contact with water may be dispersed into the matrixtogether with the active ingredients and excipients.

As the preparation method, they can be prepared by methods such as spraydry, spray chilling and melt granulation.

The controlled release tablet, granule or fine granule may be a tablet,granule or fine granule wherein a material which becomes viscous bycontact with water, such as polyethylene oxide (PEO, for example, PolyoxWSR 303 (molecular weight: 7000000), Polyox WSR Coagulant (molecularweight: 5000000), Polyox WSR 301 (molecular weight: 4000000), Polyox WSRN-60K (molecular weight: 2000000), and Polyox WSR 205 (molecular weight:600000); manufactured by Dow Chemical Co., Ltd.), hydroxypropylmethylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose90SH30000; manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylcellulose (CMC-Na, Sanlose F-1000MC), hydroxypropyl cellulose (HPC, forexample, HPC-H manufactured by Nippon Soda Co., Ltd.), hydroxyethylcellulose (HEC), carboxyvinyl polymer (HIVISWAKO (R) 103, 104, 105:manufactured by Wako Pure Chemical Industries Ltd.; CARBOPOL 943manufactured by Goodrich Co., Ltd.), chitosan, sodium alginate andpectin, is coated on the active ingredient release-controlled tablet,granule or fine granule thus obtained. These materials which becomeviscous by contact with water may be coexisted in one preparation suchas a capsule and the like as well as using for coat.

The tablet, granule or fine granule of the present invention wherein therelease of active ingredient is controlled may be a form having theabove-mentioned various kinds of release-controlled coating-layers,release-controlled matrixes and the like in combination.

As the size of tablet, granule or fine granule wherein the release ofactive ingredient is controlled, particles having a particle size of 50μm to 5 mm, preferably 100 μm to 3 mm and more preferably 100 μm to 2 mmare used. Granules or fine granules having a particle size of about 100μm to 1500 μm are most preferred.

Further, additives such as excipients for providing preparations (forexample, glucose, fructose, lactose, sucrose, D-mannitol, erythritol,multitol, trehalose, sorbitol, corn starch, potato starch, wheat starch,rice starch, crystalline cellulose, silicic acid anhydride, calciummetaphosphorate, sedimented calcium carbonate, calcium silicate, and thelike), binders (for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, methyl cellulose, polyvinylalcohol, carboxymethyl cellulose sodium, partial a starch, a starch,sodium alginate, pullulan, gum arabic powder, gelatin and the like),disintegrants (for example, low substituted hydroxypropyl cellulose,carmelose, carmelose calcium, carboxymethylstarch sodium, crosscarmelose sodium, crosspovidon, hydroxypropylstarch and the like),flavoring agents (for example, citric acid, ascorbic acid, tartaricacid, malic acid, aspartame, acesulfam potassium, thaumatin, saccharinsodium, glycyirrhizin dipotassium, sodium glutamate, sodium5′-inosinate, sodium 5′-guanylate and the like), surfactants (forexample, polysolvate (polysolvate 80 and the like),polyoxyethylene-polyoxypropylene copolymer, sodium laurylsulfate and thelike), perfumes (for example, lemon oil, orange oil, menthol, peppermintoil and the like), lubricants (for example, magnesium stearate, sucrosefatty acid eater, sodium stearylfumarate, stearic acid, talc,polyethylene glycol and the like), colorants (for example, titaniumoxide, edible Yellow No. 5, edible Blue No. 2, iron (III) oxide, yellowiron (III) oxide, and the like), antioxidants (for example, sodiumascorbate, L-cysteine, sodium bisulfate, and the like), masking agents(for example, titanium oxide and the like), and antistatic agents (forexample, talc, titanium oxide and the like) can be used.

The particle diameter of raw materials used here are not particularlylimited, and particles having a diameter of about 500 μm or less arepreferred from the viewpoint of productivity and dosing.

The tablet, granule or fine granule thus obtained may be administratedas it is by mixing with a digestive tract retentive gel-forming polymer,or can be formulated as a capsule by filling in capsules. The amount ofthe gel-forming polymer being retentive in the digestive tract is 0.1%to 100% relative to the controlled release tablet, granule or finegranule, preferably 2% to 50%, more preferably 10% to 40%, and furthermore preferably 10% to 35%.

The pharmaceutical composition of the present invention thus obtained isa composition having a extended activity of drug by a release-controlledsystem wherein therapeutic effect is revealed for at least 6 hours,preferably 8 hours, more preferably 12 hours and further preferably 16hours.

The active ingredients are not particularly limited, and can be appliedirrespective of the region of drug efficacy. Exemplified areanti-inflammatory drugs such as indomethacin and acetaminophen,analgesics such as morphine, cardiovascular agonists such as diazepamand diltiazepam, anti-histamines such as chlorophenylamine maleate,antitumors such as fluorouracil and aclarubicin, narcotics such asmidazolam, anti-hemostasis agents such as ephedrine, diuretics such ashydrochlorothiazide and furosemide, bronchodilators such as theophyline,antitussives such as codeine, antiarrythmic agents such as quinidine anddizoxin, antidiabetics such as tolbutamide, pioglitazone andtroglitazone, vitamins such as ascorbic acid, anticonvulsants such asphenitoin, local anesthetics such as lidocaine, adrenocortical hormonessuch as hydrocortisone, drugs effective for central nerve such as eisai,hypolipidemic drugs such as pravastatin, antibiotics such as amoxicillinand cephalexin, digestive tract exitomotory agents such as mosapride andcisapride, H2 blockers such as famotidine, ranitidine and cimetidinewhich are the remedies of gastritis, symptomatic gastroesophageal refluxdisease, and gastric and duodenal ulcers, and benzimidazole proton pumpinhibitors (PPI) represented by lansoprazole and optically activeisomers thereof (R-isomer and S-isomer, preferably R-isomer(hereinafter, occasionally referred to as Compound A)), omeprazole andoptically active isomers thereof (S-isomer: S omeprazole), rabeprazoleand optically active isomers thereof, pantoprazole and optically activeisomers thereof and the like, and imidazopyridine PPI represented bytenatoprazole and the like.

According to the present invention, the preparations which contain, asan active ingredient, a PPI such as acid-labile imidazole compoundsrepresented by the following general formula (I′) such as lansoprazoleand optically active isomers thereof, in particular, acid-labilebenzimidazole compounds represented by the following formula (I), andrelatively acid-stable imidazole compound derivatives (prodrug type PPI)represented by the following general formula (II) or (III) or saltsthereof or optically active isomers thereof have an excellentsustainability of drug efficacy. As a result, dosing compliance is alsoimproved and therapeutic effect is increased.

Wherein ring C′ indicates a benzene ring optionally having a substituentgroup or an aromatic monocyclic heterocyclic ring optionally having asubstituent group; R⁰ indicates a hydrogen atom, an aralkyl groupoptionally having substituent group, an acyl group or an acyloxy group;R¹, R² and R³ are the same or different and indicate a hydrogen atom, analkyl group optionally having a substituent group, an alkoxy groupoptionally having a substituent group or an amino group optionallyhaving a substituent group, respectively; and Y indicates a nitrogenatom or CH.

Among the compounds represented by the above-mentioned formula (I′), thecompound in which the ring C′ is a benzene ring optionally having asubstituent group is particularly represented by the following formula(I).

Namely, in the formula (I), ring A indicates a benzene ring optionallyhaving a substituent group, and R⁰, R¹, R², R³ and Y have the samemeaning as in the above-mentioned formula (I′).

In the above-mentioned formula (I), the preferable compound is acompound wherein ring A is a benzene ring which may have a substituentgroup selected from a halogen atom, an optionally halogenated C₁₋₄ alkylgroup, an optionally halogenated C₁₋₄ alkoxy group and a 5- or6-membered heterocyclic group; R⁰ is a hydrogen atom, an optionallysubstituted aralkyl group, an acyl group or an acyloxy group; R¹ is aC₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy group or a di-C₁₋₆alkylamino group; R² is a hydrogen atom, a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup, or an optionally halogenated C₁₋₆ alkoxy group; R³ is a hydrogenatom or a C₁₋₆ alkyl group, and Y is a nitrogen atom.

In particular, the preferable compound is a compound represented by theformula (Ia);

wherein R¹ indicates a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group; R²indicates a C₁₋₃ alkoxy group which may be halogenated or may besubstituted with a C₁₋₃ alkoxy group; R³ indicates a hydrogen atom or aC₁₋₃ alkyl group, and R⁴ indicates a hydrogen atom, an optionallyhalogenated C₁₋₃ alkoxy group or a pyrrolyl group (for example, 1-, 2-or 3-pyrrolyl group).

In the formula (Ia), the compound wherein R¹ is a C₁₋₃ alkyl group; R²is an optionally halogenated C₁₋₃ alkoxy group; R³ is a hydrogen atomand R⁴ is a hydrogen atom or an optionally halogenated C₁₋₃ alkoxy groupis particularly preferred.

In the compound represented by the above-mentioned formula (I)(hereinafter, referred to as Compound (I)), the “substituent group” ofthe “benzene ring optionally having a substituent group” represented byring A includes, for example, a halogen atom, a nitro group, an alkylgroup optionally having a substituent group, a hydroxy group, an alkoxygroup optionally having a substituent group, an aryl group, an aryloxygroup, a carboxy group, an acyl group, an acyloxy group, a 5- to10-membered heterocyclic group and the like. The benzene ring may besubstituted with about 1 to 3 of these substituent groups. When thenumber of substituents is 2 or more, each substituent groups may be thesame or different. Among these substituent groups, a halogen atom, analkyl group optionally having a substituent group, an alkoxy groupoptionally having a substituent group and the like are preferred.

The halogen atom includes fluorine, chlorine, bromine atom and the like.Among these, fluorine is preferred.

As the “alkyl group” of the “alkyl group optionally having a substituentgroup”, for example, a alkyl group (for example, a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, heptyl group and the like) is exemplified. As the “substituentgroup” of the “alkyl group optionally having a substituent group”, forexample, a halogen atom, a hydroxy group, a C₁₋₆ alkoxy group (forexample, methoxy, ethoxy, propoxy, butoxy and the like), a C₁₋₆alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and the like), a carbamoyl group and the like can beexemplified, and the number of these substituent groups may be about 1to 3. When the number of substituent group is 2 or more, eachsubstituent groups may be the same or different.

The “alkoxy group” of the “alkoxy group optionally having a substituentgroup” includes, for example, a C₁₋₆ alkoxy group (for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and the like)and the like. The “substituent group” of the “alkoxy group optionallyhaving a substituent group” are exemplified by those for theabove-mentioned “substituent group” of the “alkyl group optionallyhaving a substituent group”, and the number of the substituent group isthe same.

The “aryl group” include, for example, a C₆₋₁₄ aryl group (for example,a phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl group and thelike) and the like.

The “aryloxy group” includes, for example, a C₆₋₁₄ aryloxy group (forexample, a phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like) and thelike.

The “acyl group” includes, for example, a formyl, alkylcarbonyl,alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylsulfinyl, alkylsulfonylgroup and the like.

The “alkylcarbonyl group” includes, a C₁₋₆ alkyl-carbonyl group (forexample, acetyl, propionyl group and the like) and the like.

The “alkoxycarbonyl group” includes, for example, a C₁₋₆ alkoxy-carbonylgroup (for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl group and the like) and the like.

The “alkylcarbamoyl group” include, a N—C₁₋₆ alkyl-carbamoyl group (forexample, methylcarbamoyl, ethylcarbamoyl group and the like), a.N,N-diC₁₋₆ alkyl-carbamoyl group (for example, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl group and the like), and the like.

The “alkylsulfinyl group” includes, for example, a C₁₋₇ alkylsulfinylgroup (for example, a methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl group and the like) and the like.

The “alkylsulfonyl group” includes, for example, a C₁₋₇ alkylsulfonylgroup (for example, a methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl group and the like) and the like.

The “acyloxy group” includes, for example, an alkylcarbonyloxy group, analkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxygroup, an alkylsulfinyloxy group, an alkylsulfonyloxy group and thelike.

The “alkylcarbonyloxy group” includes, a C₁₋₆ alkyl-carbonyloxy group(for example, acetyloxy, propionyloxy group and the like) and the like.

The “alkoxycarbonyloxy group” includes, for example, a C₁₋₆alkoxy-carbonyloxy group (for example, methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy group and thelike) and the like.

The “alkylcarbamoyloxy group” includes, a C₁₋₆ alkyl-carbamoyloxy group(for example, methylcarbamoyloxy, ethylcarbamoyloxy group and the like)and the like.

The “alkylsulfinyloxy group” includes, for example, a C₁₋₇alkylsulfinyloxy group (for example, methylsulfinyloxy,ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy group and thelike) and the like.

The “alkylsulfonyloxy group” includes, for example, a C₁₋₇alkylsulfonyloxy group (for example, methylsulfonyloxy,ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy group and thelike) and the like.

The 5- to 10-membered heterocyclic group include, for example, a 5- to10-membered (preferably 5- or 6-membered) heterocyclic group whichcontains one or more (for example, one to three) hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in addition to acarbon atom. Specific example includes 2- or 3-thienyl group, 2-, 3- or4-pyridyl group, 2- or 3-furyl group, 1-, 2- or 3-pyrrolyl group, 2-,3-, 4-, 5- or 8-quinolyl group, 1-, 3-, 4- or 5-isoquinolyl group, 1-,2- or 3-indolyl group. Among these, 5- or 6-membered heterocyclic groupssuch as 1-, 2- or 3-pyrrolyl groups are preferred.

Ring A is preferably a benzene ring which may have 1 or 2 substituentgroups selected from a halogen atom, an optionally halogenated C₁₋₄alkyl group, an optionally halogenated C₁₋₄ alkoxy-group and 5- or6-membered heterocyclic group.

In the above-mentioned formula (I′), the “aromatic monocyclicheterocyclic ring” of the “optionally substituted aromatic monocyclicheterocyclic ring” represented by ring C′ includes, for example, 5- to6-membered aromatic monocyclic heterocyclic rings such as furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine and triazine. As the “aromaticmonocyclic heterocyclic ring” represented by ring C′, “a benzene ringwhich may have a substituent group” represented by the above-mentionedring A and “a pyridine ring optionally having a substituent group” areparticularly preferred. The “pyridine ring optionally having asubstituent group” represented by ring C′ may have 1 to 4 of the samesubstituent groups as those exemplified with respect to the “benzenering which may have a substituent group” represented by theabove-mentioned ring A at substitutable positions.

The position wherein “aromatic monocyclic heterocyclic ring” of the“aromatic monocyclic heterocyclic ring optionally having a substituentgroup” is condensed with an imidazole moiety is not specificallylimited.

In the above-mentioned formula (I′) or (I), the “aralkyl group” of the“aralkyl group optionally having a substituent group” represented by R⁰includes, for example, a C₇₋₁₆ aralkyl group (for example, C₆₋₁₀arylC₁₋₆ alkyl group such as benzyl and phenethyl and the like) and thelike. Examples of the “substituent group” of the “aralkyl groupoptionally having a substituent group” include the same groups as thoseexemplified with respect to the “substituent group” of theabove-mentioned “alkyl group optionally having a substituent group”, andthe number of the substituent groups is 1 to about 4. When the number ofthe substituent group is 2 or more, each substituent groups may be thesame or different.

The “acyl group” represented by R⁰ includes, for example, the “acylgroup” described as the substituent group of the above-mentioned ring A.

The “acyloxy group” represented by R⁰ includes, for example, the“acyloxy group” described as the substituent group of theabove-mentioned ring A.

The preferable R⁰ is a hydrogen atom.

In the above-mentioned formula (I′) or (I), the “alkyl group optionallyhaving a substituent group” represented by R¹, R² or R³ includes the“alkyl group optionally having a substituent group” described as thesubstituent group of the above-mentioned ring A.

The “alkoxy group optionally having a substituent group” represented byR¹, R² or R³ includes the “alkoxy group optionally having a substituentgroup” described as the substituent group of the above-mentioned ring A.

The “amino group optionally having a substituent group” represented byR⁰, R² or R³ includes, for example, an amino group, a mono-C₁₋₆alkylamino group (for example, methylamino, ethylamino and the like), amono-C₆₋₁₄ arylamino group (for example, phenylamino, 1-naphthylamino,2-naphthylamino and the like), a di-C₁₋₆ alkylamino group (for example,dimethylamino, diethylamino and the like), a di-C₆₋₁₄ arylamino group(for example, diphenylamino and the like) and the like.

The preferable R¹ is a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkoxy-C₁₋₆ alkoxy group and a di-C₁₋₆ alkylamino group. Furtherpreferable R² is a C₁₋₃ alkyl group or a C₁₋₃ alkoxy group.

The preferable R² is a hydrogen atom, a C₁₋₆ alkoxy-C₁₋₆ alkoxy group oran optionally halogenated C₁₋₆ alkoxy group. Further preferable R³ is aC₁₋₃ alkoxy group which may be optionally halogenated or may beoptionally substituted with a C₁₋₃ alkoxy group.

The preferable R³ is a hydrogen atom or a C₁₋₆ alkyl group. Furtherpreferable R³ is a hydrogen atom or a C₁₋₃ alkyl group (in particular, ahydrogen atom).

The preferable Y is a nitrogen atom.

As the specific example of the compound (I), the following compounds areexemplified.

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(lansoprazole),2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole,2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolesodium salt,5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand the like.

Among these compounds, lansoprazole, namely2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleis preferable in particular.

The present invention is preferably applied to the PPI ofimidazopyridine compound in addition to the PPI of the above-mentionedbenzimidazole compound. As the PPI of the imidazopyridine compound, forexample, tenatoprazole is exemplified.

Further, the above-mentioned compound (I) and compound (I′) includingthe imidazopyridine compound may be racemic, and optically activecompounds such as R-isomer and S-isomer. For example, the opticallyactive compounds such as optically active compound of lansoprazole, thatis,(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleand(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleare preferable for the present invention in particular. Further, forlansoprazole, lansoprazole R-isomer and lansoprazole S-isomer, crystalsare usually preferred, but since they are stabilized by preparationitself as described later and stabilized by compounding a basicinorganic salt and further providing an intermediate layer, those beingamorphous as well as crystalline can be also used.

The salt of compound (I′) and compound (I) is preferably apharmacologically acceptable salt, and for example, a salt with aninorganic base, a salt with an organic base, a salt with a basic aminoacid and the like are mentioned.

The preferable salt with an inorganic base includes, for example, alkalimetal salts such as sodium salt and potassium salt; alkali earth metalsalts such as calcium salt and magnesium salt; ammonium salt and thelike.

The preferable example of the salt with an organic base includes, forexample, salts with an alkylamine (trimethylamine, triethylamine and thelike), a heterocyclic amine (pyridine, picoline and the like), analkanolamine (ethanolamine, diethanolamine, triethanolamine and thelike), dicyclohexylamine, N,N′-dibenzylethylenediamine and the like.

The preferable example of the salt with a basic amino acid includes, forexample, salts with arginine, lysine, ornithine and the like.

Among these salts, an alkali metal salt and an alkali earth metal saltare preferred. A sodium salt is preferred particularly.

The compound (I′) or (I) can be produced by known methods, and areproduced by methods disclosed in, for example, JP-A 61-50978, U.S. Pat.No. 4,628,098, JP-A 10-195068, WO 98/21201, JP-A 52-62275, JP-A54-141783 and the like, or analogous methods thereto. Further, theoptically active compound (I) can be obtained by optical resolutionmethods (a fractional recrystallization method, a chiral column method,a diastereomer method, a method using microorganism or enzyme, and thelike) and an asymmetric oxidation method, etc. Further, lansoprazoleR-isomer can be produced according to production methods described in,for example, WO 00-78745, WO 01/83473 and the like.

The benzimidazole compound having antitumor activity used in the presentinvention is preferably lansoprazole, omeprazole, rabeprazole,pantoprazole, leminoprazole, tenatoprazole (TU-199) and the like, oroptically active compounds thereof and pharmacologically acceptablesalts thereof. Lansoprazole or an optically active compound thereof, inparticular R-isomer is preferred. Lansoprazole or an optically activecompound thereof, in particular R-isomer is preferably in a form ofcrystal, but may be an amorphous form. Further, they are also suitablyapplied to the prodrug of these PPIs.

Examples of these preferable prodrugs include the compound representedby the following general formula (II) and (III) in addition to theprodrug which is included in compound (I) or (I′).

In the compound represented by the above formula (II) (hereinafter,referred to as compound (II)), ring B designates a “pyridine ringoptionally having substituents”.

The pyridine ring of the “pyridine ring optionally having substituents”represented by ring B may have 1 to 4 substituents at substitutablepositions thereof. As the substituent, for example, a halogen atom(e.g., fluorine, chlorine, bromine, iodine etc.), a hydrocarbon groupoptionally having substituents (e.g., alkyl group having 1 to 6 carbonatoms such as methyl group, ethyl group, n-propyl group etc., and thelike), an amino group optionally having substituents (e.g., amino; aminogroup mono- or di-substituted by alkyl group having 1 to 6 carbon atoms,such as methylamino, dimethylamino, ethylamino, diethylamino group etc.,and the like), an amide group (e.g., C₁₋₃ acylamino group such asformamide, acetamide etc., and the like), a lower alkoxy groupoptionally having substituents (e.g., alkoxy group having 1 to 6 carbonatoms such as methoxy, ethoxy, 2,2,2-trifluoroethoxy, 3-methoxypropoxygroup and the like), a lower alkylenedioxy group (e.g., C₁₋₃alkylenedioxy group such as methylenedioxy, ethylenedioxy etc., and thelike) and the like can be mentioned.

As the substituent, which is the substituent of the “pyridine ringoptionally having substituents” represented by ring B can have, forexample, a halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl group and the like), a lower alkenyl group(e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allylgroup and the like), a lower alkynyl group (e.g., alkynyl group having 2to 6 carbon atoms such as ethynyl, propargyl group and the like), acycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like),a lower alkoxy group (e.g., alkoxy group having 1 to 6 carbon atoms suchas methoxy, ethoxy group and the like), a nitro group, a cyano group, ahydroxy group, a thiol group, a carboxyl group, a lower alkanoyl group(e.g., formyl; C₁-C₆ alkyl-carbonyl group, such as acetyl, propionyl,butyryl group and the like), a lower alkanoyloxy group (e.g., formyloxy;C₁-C₆ alkyl-carbonyloxy group, such as acetyloxy, propionyloxy group andthe like), a lower alkoxycarbonyl group (e.g., C₁-C₆ alkoxy-carbonylgroup, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl groupand the like), an aralkyloxycarbonyl group (e.g., C₇-C₁₁aralkyloxy-carbonyl group, such as benzyloxycarbonyl group and thelike), an aryl group (e.g., aryl group having 6 to 14 carbon atoms suchas phenyl, naphthyl group and the like), an aryloxy group (e.g., aryloxygroup having 6 to 14 carbon atoms such as phenyloxy, naphthyloxy groupand the like), an arylcarbonyl group (e.g., C₆-C₁₄ aryl-carbonyl group,such as benzoyl, naphthoyl group and the like), an arylcarbonyloxy group(e.g., C₆-C₁₄ aryl-carbonyloxy group, such as benzoyloxy, naphthoyloxygroup and the like), a carbamoyl group optionally having substituents(e.g., carbamoyl; carbamoyl group mono- or di-substituted by alkyl grouphaving 1 to 6 carbon atoms, such as methylcarbamoyl, dimethylcarbamoylgroup etc., and the like), an amino group optionally having substituents(e.g., amino; amino group mono- or di-substituted by alkyl group having1 to 6 carbon atoms, such as methylamino, dimethylamino, ethylamino,diethylamino group etc., and the like) and the like, can be mentioned,wherein the number of substituents and the position of the substitutionare not particularly limited.

While the number of substituents and the position of substitution of the“pyridine ring optionally having substituents” represented by ring B arenot particularly limited, 1 to 3 substituents mentioned above preferablysubstitute any of the 3-, 4- and 5-positions of the pyridine ring.

As the “pyridine ring optionally having substituents” represented byring B, 3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl is preferable.

In the present invention, ring C represents a “benzene ring optionallyhaving substituents” or an “aromatic monocyclic heterocycle optionallyhaving substituents”, which is condensed with an imidazole part. Ofthese, the former is preferable.

The benzene ring of the “benzene ring optionally having substituents”represented by ring C may have 1 to 4 substituents at substitutablepositions thereof. As the substituent, for example, a halogen atom(e.g., fluorine, chlorine, bromine, iodine etc.), a hydrocarbon groupoptionally having substituents (e.g., alkyl group having 1 to 6 carbonatoms selected from methyl group, ethyl group, n-propyl group etc., andthe like), an amino group optionally having substituents (e.g., amino;amino group mono- or di-substituted by alkyl group having 1 to 6 carbonatoms, such as methylamino, dimethylamino, ethylamino, diethylaminogroup etc., and the like), an amide group (e.g., C₁₋₃ acylamino groupsuch as formamide, acetamide etc., and the like), a lower alkoxy groupoptionally having substituents (e.g., alkoxy group having 1 to 6 carbonatoms, such as methoxy, ethoxy, difluoromethoxy group etc., and thelike), a lower alkylenedioxy group (e.g., C₁₋₃ alkylenedioxy group suchas methylenedioxy, ethylenedioxy etc., and the like), and the like canbe mentioned.

As the substituent, which is the substituent of the “benzene ringoptionally having substituents” represented by ring C can have, forexample, a halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl group and the like), a lower alkenyl group(e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allylgroup and the like), a lower alkynyl group (e.g., alkynyl group having 2to 6 carbon atoms such as ethynyl, propargyl group and the like), acycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like),a lower alkoxy group (e.g., alkoxy group having 1 to 6 carbon atoms suchas methoxy, ethoxy group and the like), a nitro group, a cyano group, ahydroxy group, a thiol group, a carboxyl group, a lower alkanoyl group(e.g., formyl; C₁₋₆ alkyl-carbonyl group, such as acetyl, propionyl,butyryl group and the like), a lower alkanoyloxy group (e.g., formyloxy;C₁₋₆ alkyl-carbonyloxy group, such as acetyloxy, propionyloxy group andthe like), a lower alkoxycarbonyl group (e.g., C₁₋₆ alkoxy-carbonylgroup, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl groupand the like), an aralkyloxycarbonyl group (e.g., C₇₋₁₇aralkyloxy-carbonyl group, such as benzyloxycarbonyl group and thelike), an aryl group (e.g., aryl group having 6 to 14 carbon atoms suchas phenyl, naphthyl group and the like), an aryloxy group (e.g., aryloxygroup having 6 to 14 carbon atoms such as phenyloxy, naphthyloxy groupand the like), an arylcarbonyl group (e.g., C₆₋₁₄ aryl-carbonyl group,such as benzoyl, naphthoyl group and the like), an arylcarbonyloxy group(e.g., C₆₋₁₄ aryl-carbonyloxy group, such as benzoyloxy, naphthoyloxygroup and the like), a carbamoyl group optionally having substituents(e.g., carbamoyl; carbamoyl group mono- or di-substituted by alkyl grouphaving 1 to 6 carbon atoms such as methylcarbamoyl, dimethylcarbamoylgroup etc., and the like), an amino group optionally having substituents(e.g., amino; amino group mono- or di-substituted by alkyl group having1 to 6 carbon atoms such as methylamino, dimethylamino, ethylamino,diethylamino group etc., and the like) and the like can be mentioned,wherein the number of substituents and the position of the substitutionare not particularly limited.

As the “benzene ring optionally having substituents” represented by ringC, a benzene ring is preferable.

As the “aromatic monocyclic heterocycle” of the “aromatic monocyclicheterocycle optionally having substituents” represented by ring C, forexample, a 5- or 6-membered aromatic monocyclic heterocycle such asfuran, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetraxole, pyridine,pyridazine, pyrimidine, pyrazine, triazine etc., and the like can bementioned. As the “aromatic monocyclic heterocycle” represented by ringC, a pyridine ring is particularly preferable. It may have, atsubstitutable positions thereof, 1 to 4 substituents similar to thosefor the “benzene ring optionally having substituents” represented byring C.

The position where the “aromatic monocyclic heterocycle” of the“aromatic monocyclic heterocycle optionally having substituents” iscondensed with the imidazole part is not particularly limited.

In the present invention, X₁ and X₂ represent an oxygen atom and asulfur atom, respectively. Both X₁ and X₂ preferably represent an oxygenatom.

In the present invention, W represents a “divalent chain hydrocarbongroup optionally having substituents”, or the formula:—W₁—Z—W₂—wherein W₁ and W₂ are each a “divalent chain hydrocarbon group” or abond, and Z is a divalent group such as a “divalent hydrocarbon ringgroup optionally having substituents”, a “divalent heterocyclic groupoptionally having substituents”, an oxygen atom, SO_(n) wherein n is 0,1 or 2 or >N-E wherein E is a hydrogen atom, a hydrocarbon groupoptionally having substituents, a heterocyclic group optionally havingsubstituents, a lower alkanoyl group, a lower alkoxycarbonyl group, anaralkyloxycarbonyl group, a thiocarbamoyl group, a lower alkylsulfinylgroup, a lower alkylsulfonyl group, a sulfamoyl group, a mono-loweralkylsulfamoyl group, a di-lower alkylsulfamoyl group, an arylsulfamoylgroup, an arylsulfinyl group, an arylsulfonyl group, an arylcarbonylgroup, or a carbamoyl group optionally having substituents, when Z is anoxygen atom, SO_(n) or >N-E, W₁ and W₂ are each a “divalent chainhydrocarbon group”. Particularly, W is preferably a “divalent chainhydrocarbon group optionally having substituents”.

As the “divalent chain hydrocarbon group” of the “divalent chainhydrocarbon group optionally having substituents” represented by W and“divalent chain hydrocarbon group” represented by W₁ and W₂, forexample, C₁₋₆ alkylene group (e.g., methylene, ethylene, trimethyleneetc.), a C₂₋₆ alkenylene group (e.g., ethenylene etc.), a C₂₋₆alkynylene group (e.g., ethynylene etc.) and the like can be mentioned.The divalent chain hydrocarbon group for W may have 1 to 6 substituentssimilar to those for the “benzene ring optionally having substituents”represented by ring C at substitutable positions thereof.

As the “divalent chain hydrocarbon group” of the “divalent chainhydrocarbon group optionally having substituents” represented by W and“divalent chain hydrocarbon group” represented by W₁ and W₂, a methylenegroup and an ethylene group are preferable. As W, an ethylene group isparticularly preferable. When Z is an oxygen atom, SO_(n) or >N-E (n andE are as defined above), the “divalent chain hydrocarbon group”represented by W₁ is preferably a hydrocarbon group having 2 or morecarbon atoms.

As the “hydrocarbon ring” of the “divalent hydrocarbon ring groupoptionally having substituents” represented by Z, for example, analicyclic hydrocarbon ring, an aromatic hydrocarbon ring and the likecan be mentioned, with preference given to one having 3 to 16 carbonatoms, which may have 1 to 4 substituents similar to those for the“benzene ring optionally having substituents” represented by ring C atsubstitutable positions thereof. As the hydrocarbon ring, for example,cycloalkane, cycloalkene, arene and the like are used.

As a cycloalkane in the “divalent hydrocarbon ring group optionallyhaving substituents” represented by Z, for example, a lower cycloalkaneand the like are preferable, and, for example, C₃₋₁₀ cyclcalkane such ascyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, bicyclo[2.2.1]heptane, adamantane etc., and the like aregenerally used.

As a cycloalkene in the “divalent hydrocarbon ring group optionallyhaving substituents” represented by Z, for example, a lower cycloalkeneis preferable, and, for example, C₄₋₉ cycloalkene such as cyclopropene,cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene etc.,and the like are generally used.

As an arene in the “divalent hydrocarbon ring group optionally havingsubstituents” represented by Z, for example, a C₆₋₁₄ arene such asbenzene, naphthalene, phenanthrene etc., and the like are preferable,and, for example, phenylene and the like are generally used.

As a heterocycle in the “divalent heterocyclic group optionally havingsubstituents” represented by Z, a 5- to 12-membered “aromaticheterocycle” or “saturated or unsaturated non-aromatic heterocycle”containing, as ring-constituting atom (ring atom), 1 to 3 (preferably 1or 2) kinds of at least 1 (preferably 1 to 4, more preferably 1 or 2)hetero atoms selected from oxygen atom, sulfur atom and nitrogen atometc., and the like can be mentioned, which may have 1 to 4 substituentssimilar to those for the “benzene ring optionally having substituents”represented by ring C at substitutable positions thereof.

As an aromatic heterocycle in the “divalent heterocyclic groupoptionally having substituents” represented by Z, an aromatic monocyclicheterocycle, an aromatic fused heterocycle and the like can bementioned.

As the “aromatic monocyclic heterocycle”, for example, a 5- or6-membered aromatic monocyclic heterocycle such as furan, thiophene,pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,triazine etc., and the like can be mentioned.

As the “aromatic fused heterocycle”, for example, a 8- to 12-memberedaromatic fused heterocycle such as benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole,benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole,1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline,cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine,pteridine, carbazole, carboline, acridine, phenoxazine, phenothiazine,phenazine, phenoxathiin, thianthrene, phenanthridine, phenanthroline,indolizine, pyrrolo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine,imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrimidine,1,2,4-triazolo[4,3-a]pyridine, 1,2,4-triazolo[4,3-b]pyridazine etc., andthe like can be mentioned.

As a saturated or unsaturated non-aromatic heterocycle in the “divalentheterocyclic group optionally having substituents” represented by Z, forexample, a 3- to 8-membered (preferably 5- or 6-membered) saturated orunsaturated (preferably saturated) non-aromatic heterocycle (aliphaticheterocycle) such as oxylane, azetidine, oxetane, thietane, pyrrolidine,tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran,tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, azepane,oxepane, thiene, oxazepane, thiazepane, azocane, oxocane, thiocane,oxazocane, thiazocane etc., and the like can be mentioned.

These may be oxo-substituted and may be, for example, 2-oxoazetidine,2-oxopyrrolidine, 2-oxopiperidine, 2-oxazepane, 2-oxazocane,2-oxotetrahydrofuran, 2-oxotetrahydropyran, 2-oxotetrahydrothiophene,2-oxothiane, 2-oxopiperazine, 2-oxooxepane, 2-oxooxazepane,2-oxothiepane, 2-oxothiazepane, 2-oxooxocane, 2-oxothiocane,2-oxooxazocane, 2-oxothiazocane and the like.

The two bonds from the “hydrocarbon ring group” of the “divalenthydrocarbon ring group optionally having substituents” or the“heterocyclic group” of the “divalent heterocyclic group optionallyhaving substituents” represented by Z may be present at any possibleposition.

The “hydrocarbon group optionally having substituents” and “heterocyclicgroup optionally having substituents” represented by E is as defined inthe following.

As the “lower alkanoyl group” represented by E, for example, formyl, aC₁₋₆ alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryletc., and the like can be used.

As the “lower alkoxycarbonyl group” represented by E, for example, aC₁₋₆ alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl etc., and the like are used.

As the “aralkyloxycarbonyl” represented by E, for example, a C₇₋₁₁aralkyloxy-carbonyl group such as benzyloxycarbonyl etc., and the likeare used.

As the “lower alkylsulfinyl group” represented by E, for example, a C₁₋₆alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl etc., and thelike are used.

As the “lower alkylsulfonyl group” represented by E, for example, a C₁₋₆alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl etc., and thelike are used.

As the “mono-lower alkylsulfamoyl group” represented by E, for example,a mono-C₁₋₆ alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyletc., and the like are used.

As the “di-lower alkylsulfamoyl group” represented by E, for example, adi-C₁₋₆ alkylsulfamoyl group such as dimethylsulfamoyl, diethylsulfamoyletc., and the like are used.

As the “arylsulfamoyl group” represented by E, for example, a C₆₋₁₀arylsulfamoyl group such as phenylsulfamoyl, naphthylsulfamoyl etc., andthe like are used.

As the “arylsulfinyl group” represented by E, for example, a C₆₋₁₀arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl etc., andthe like are used.

As the “arylsulfonyl group” represented by E, for example, a C₆₋₁₀arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl etc., andthe like are used.

As the “arylcarbonyl group” represented by E, for example, C₆₋₁₀aryl-carbonyl group such as benzoyl, naphthoyl etc., and the like areused.

The “carbamoyl group optionally having substituents” represented by Eis, for example, a group of the formula —CONR₂R₃ wherein R₂ and R₃ areeach a hydrogen atom, a hydrocarbon group optionally having substituentsor a heterocyclic group optionally having substituents, and in theformula —CONR₂R₃, R₂ and R₃ may form a ring together with the adjacentnitrogen atom, and the like.

In the present invention, R is a “hydrocarbon group optionally havingsubstituents” or a “heterocyclic group optionally having substituents”,and R can be bonded to W. Of these, a C₁₋₆ hydrocarbon group optionallyhaving substituents is preferable and a lower (C₁₋₆) alkyl group isparticularly preferable. The “hydrocarbon group optionally havingsubstituents” and “heterocyclic group optionally having substituents”represented by R are as defined in the following. A detailed explanationof the case where R is bonded to W is given in the following.

In the present invention, D₁ and D₂ are each a bond, an oxygen atom, asulfur atom or >NR₁, and in the formula, R₁ is a hydrogen atom or ahydrocarbon group optionally having substituents. However, the presentinvention excludes a case where D₁ and D₂ are both respectively a bond.Among others, each of D₁ and D₂ is preferably a bond or an oxygen atom,and particularly preferably, D₁ is an oxygen atom and D₂ is an oxygenatom or a bond. The “hydrocarbon group optionally having substituents”represented by R₁ is as defined in the following.

In the present invention, G is a “hydrocarbon group optionally havingsubstituents” or a “heterocyclic group optionally having substituents”.Of these, a C₁₋₆ hydrocarbon group optionally having substituents or asaturated heterocyclic group optionally having substituents, whichcontains, as ring-constituting atom, 1 to 4 hetero atoms selected fromoxygen atom, sulfur atom and nitrogen atom is preferable. As G, amongothers, a hydrocarbon group optionally having substituents or asaturated oxygen-containing heterocyclic group optionally havingsubstituents, which further contains, as ring-constituting atom, 1 to 3hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom ispreferable. The “hydrocarbon group optionally having substituents” and“heterocyclic group optionally having substituents” represented by G areas defined in the following.

As the “hydrocarbon group” of the “hydrocarbon group optionally havingsubstituents” represented by the above-mentioned E, R, R₁ and G, forexample, a saturated or unsaturated aliphatic hydrocarbon group, asaturated or unsaturated alicyclic hydrocarbon group, a saturated orunsaturated alicyclic-aliphatic hydrocarbon group, an aromatichydrocarbon group, an aromatic-saturated or unsaturated alicyclichydrocarbon group and the like can be mentioned, with preference givento those having 1 to 16, more preferably 1 to 6, carbon atoms. Specificexamples thereof include alkyl group, alkenyl group, alkynyl group,cycloalkyl group, cycloalkenyl group, cycloalkylalkyl group,cycloalkenylalkyl group, aryl group and arylalkyl group and the like.

For example, the “alkyl group” is preferably a lower alkyl group (C₁₋₆alkyl group) and the like, and, for example, a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-ethylpropyl, hexyl etc., and the like aregenerally used. For R, a lower alkyl group (C₁₋₆ alkyl group) ispreferable, particularly a methyl group is preferable.

For example, the “alkenyl group” is preferably a lower alkenyl group andthe like, and, for example, a C₂₋₇ alkenyl group such as vinyl,1-propenyl, allyl, isopropenyl, butenyl, isobutenyl,2,2-dimethyl-pent-4-enyl etc., and the like are generally used.

For example, the “alkynyl group” is preferably a lower alkynyl group andthe like, and, for example, a C₂₋₆ alkynyl group such as ethynyl,propargyl, 1-propynyl etc., and the like are generally used.

For example, the “cycloalkyl group” is preferably a lower cycloalkylgroup and the like, and, for example, a C₃₋₁₀ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptanyl and adamantyl etc., and the like aregenerally used.

For example, the “cycloalkenyl group” is preferably a lower cycloalkenylgroup, and, for example, a C₃₋₁₀ cycloalkenyl group such ascydlopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, bicyclo[2.2.1]hept-5-en-2-yl etc., and the like aregenerally used.

For example, the “cycloalkylalkyl group.” is preferably a lowercycloalkylalkyl group, and, for example, a C₄₋₉ cycloalkylalkyl groupsuch as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl and cyclohexylethyl etc., and thelike are generally used.

For example, the “cycloalkenylalkyl group” is preferably a lowercycloalkenylalkyl group, and, for example, C₄₋₉ cycloalkenylalkyl suchas cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl,cyclohexenylpropyl, cycloheptenylmethyl, cycloheptenylethyl andbicyclo[2.2.1]hept-5-en-2-ylmethyl etc., and the like are generallyused.

For example, the “aryl group” is preferably a C₆₋₁₄ aryl group such asphenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl etc., and thelike, and, for example, phenyl group and the like are generally used.

The “arylalkyl group” contains, as the aryl moiety, the “aryl group”defined above, and as the alkyl moiety, the “alkyl group” defined above.Of these, for example, a C₆₋₁₄ aryl-C₁₋₆ alkyl group is preferable, and,for example, benzyl, phenethyl and the like are generally used.

As the substituent that the “hydrocarbon group” of the “hydrocarbongroup optionally having substituents” represented by the above-mentionedE, R, R₁ and G may have, for example, a halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), a nitro group, a cyano group, a hydroxygroup, a thiol group, a sulfo group, a sulphino group, a phosphonogroup, an optionally halogenated lower alkyl group (e.g., C₁₋₆ alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-ethylpropyl, hexyl and the like, a mono-, di- ortri-halogeno-C₁₋₆ alkyl group such as chloromethyl, dichloromethyl,trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl,6,6,6-trifluorohexyl etc., and the like), an oxo group, an amidinogroup, an imino group, an alkylenedioxy group (e.g., C₁₋₃ alkylenedioxygroup such as methylenedioxy, ethylenedioxy etc., and the like), a loweralkoxy group (e.g., C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy etc., and the like),an optionally halogenated lower alkoxy group (e.g., a mono-, di- ortri-halogeno-C₁₋₆ alkoxy group such as chloromethyloxy,dichloromethyloxy, trichloromethyloxy, fluoromethyloxy,difluoromethyloxy, trifluoromethyloxy, 2-bromoethyloxy,2,2,2-trifluoroethyloxy, pentafluoroethyloxy, 3,3,3-trifluoropropyloxy,4,4,4-trifluorobutyloxy, 5,5,5-trifluoropentyloxy,6,6,6-trifluorohexyloxy etc., and the like), a lower alkylthio group(e.g., a C₁₋₆ alkylthio group such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, pentylthio, hexylthio etc., andthe like), a carboxyl group, a lower alkanoyl group (e.g., formyl; aC₁₋₆ alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryletc., and the like), a lower alkanoyloxy group (e.g., formyloxy; a C₁₋₆alkyl-carbonyloxy group such as acetyloxy, propionyloxy, butyryloxy,isobutyryloxy etc., and the like), a lower alkoxycarbonyl group (e.g., aC₁₋₆ alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl etc., and the like), aralkyloxycarbonylgroup (e.g., a C₇₋₁₁ aralkyloxy-carbonyl group such as benzyloxycarbonyletc., and the like), a thiocarbamoyl group, a lower alkylsulfinyl group(e.g., a C₁₋₆ alkylsulfinyl group such as methylsulfinyl, ethylsulfinyletc., and the like), a lower alkylsulfonyl group (e.g., a alkylsulfonylgroup such as methylsulfonyl, ethylsulfonyl etc., and the like), asulfamoyl group, a mono-lower alkylsulfamoyl group (e.g., a mono-C₁₋₆alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl etc., andthe like), di-lower alkylsulfamoyl group (e.g., a di-C₁₋₆ alkylsulfamoylgroup such as dimethylsulfamoyl, diethylsulfamoyl etc., and the like),an arylsulfamoyl group (e.g., a C₆₋₁₀ arylsulfamoyl group such asphenylsulfamoyl, naphthylsulfamoyl etc., and the like), an aryl group(e.g., a C₆₋₁₀ aryl group such as phenyl, naphthyl etc., and the like),an aryloxy group (e.g., a C₆₋₁₀ aryloxy group such as phenyloxy,naphthyloxy etc., and the like), an arylthio group (e.g., a C₆₋₁₀arylthio group such as phenylthio, naphthylthio etc., and the like), anarylsulfinyl group (e.g., a C₆₋₁₀ arylsulfinyl group such asphenylsulfinyl, naphthylsulfinyl etc., and the like), an arylsulfonylgroup (e.g., a C₆₋₁₀ arylsulfonyl group such as phenylsulfonyl,naphthylsulfonyl etc., and the like), an arylcarbonyl group (e.g., aC₆₋₁₀ aryl-carbonyl group such as benzoyl, naphthoyl etc., and thelike), an arylcarbonyloxy group (e.g., a C₆₋₁₀ aryl-carbonyloxy groupsuch as benzoyloxy, naphthoyloxy etc., and the like), an optionallyhalogenated lower alkylcarbonylamino group (e.g., an optionallyhalogenated C₁₋₆ alkyl-carbonylamino group such as acetylamino,trifluoroacetylamino etc., and the like), a carbamoyl group optionallyhaving substituents (e.g., a group of the formula —CONR₂R₃ wherein R₂and R₃ are each a hydrogen atom, a hydrocarbon group optionally havingsubstituents or a heterocyclic group optionally having substituents andin the formula —CONR₂R₃, R₂ and R₃ may form a ring together with theadjacent nitrogen atom), an amino group optionally having substituents(e.g., a group of the formula —NR₂R₃ wherein R₂ and R₃ are as definedabove and in the formula —NR₂R₃, R₂ and R₃ may form a ring together withthe adjacent nitrogen atom), a ureido group optionally havingsubstituents (e.g., a group of the formula —NHCONR₂R₃ wherein R₂ and R₃are as defined above and in the formula —NHCONR₂R₃, R₂ and R₃ may form aring together with the adjacent nitrogen atom), a carboxamide groupoptionally having substituents (e.g., a group of the formula —NR₂COR₃wherein R₂ and R₃ are as defined above), a sulfonamide group optionallyhaving substituents (e.g., a group of the formula —NR₂SO₂R₃ wherein R₂and R₃ are as defined above), a heterocyclic group optionally havingsubstituents (as defined for R₂ and R₃) and the like are used.

As the “hydrocarbon group” of the “hydrocarbon group optionally havingsubstituents” for R₂ and R₃, for example, a lower alkyl group (e.g.,alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propylgroup and the like), a lower alkenyl group (e.g., alkenyl group having 2to 6 carbon atoms such as vinyl, allyl group and the like), a loweralkynyl group (e.g., alkynyl group having 2 to 6 carbon atoms such asethynyl, propargyl group and the like), a cycloalkyl group (e.g.,cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl group and the like), a cycloalkenylgroup (e.g., cycloalkenyl group having 3 to 8 carbon atoms such ascyclobutenyl, cyclopentenyl, cyclohexenyl group and the like), acycloalkylalkyl group (e.g., C₃-C₈ cycloalkyl —C₁-C₆ alkyl group, suchas cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl group and the like), a cycloalkenylalkyl group (e.g.,C₃-C₈ cycloalkenyl —C₁-C₆ alkyl group, such as cyclobutenylmethyl,cyclopentenylmethyl, cyclohexenylmethyl group and the like), an arylgroup (e.g., aryl group having 6 to 14 carbon atoms such as phenyl,naphthyl group and the like), an arylalkyl group (e.g., C₆-C₁₄ aryl—C₁-C₆ alkyl group, such as benzyl, naphthylmethyl group and the like)and the like can be mentioned.

As the “heterocyclic group” of the “heterocyclic group optionally havingsubstituents” represented by R₂ and R₃, a 5- to 12-membered monocyclicor fused heterocyclic group containing 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom such aspyridyl, pyrrolidinyl, piperazinyl, piperidinyl, 2-oxazepinyl, furyl,decahydroisoquinolyl, quinolyl, indolyl, isoquinolyl, thienyl,imidazolyl, morpholinyl etc., and the like can be mentioned. As thesubstituent for the “hydrocarbon group optionally having substituents”and “heterocyclic group optionally having substituents” for R₂ and R₃,for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodineetc.), a lower alkyl group (e.g., alkyl group having 1 to 6 carbon atomssuch as methyl, ethyl, propyl group and the like), a lower alkenyl group(e.g., alkenyl group having 2 to 6 carbon atoms such as vinyl, allylgroup and the like), a lower alkynyl group (e.g., alkynyl group having 2to 6 carbon atoms such as ethynyl, propargyl group and the like), acycloalkyl group (e.g., cycloalkyl group having 3 to 8 carbon atoms suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like),a lower alkoxy group (e.g., alkoxy group having 1 to 6 carbon atoms suchas methoxy, ethoxy group and the like), a nitro group, a cyano group, ahydroxy group, a thiol group, a carboxyl group, a lower alkanoyl group(e.g., formyl; C₁₋₆ alkyl-carbonyl group, such as acetyl, propionyl,butyryl group and the like), a lower alkanoyloxy group (e.g., formyloxy;C₁₋₆ alkyl-carbonyloxy group, such as acetyloxy, propionyloxy group andthe like), a lower alkoxycarbonyl group (e.g., C₁₋₆ alkoxy-carbonylgroup, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl groupand the like), an aralkyloxycarbonyl group (e.g., C₇₋₁₇aralkyloxy-carbonyl group, such as benzyloxycarbonyl group and thelike), an aryl group (e.g., C₆₋₁₄ aryl group, such as phenyl, naphthylgroup and the like), an aryloxy group (e.g., C₆₋₁₄ aryloxy group having,such as phenyloxy, naphthyloxy group and the like), an arylcarbonylgroup (e.g., C₆₋₁₄ aryl-carbonyl group, such as benzoyl, naphthoyl groupand the like), an arylcarbonyloxy group (e.g., C₆₋₁₄ aryl-carbonyloxygroup, such as benzoyloxy, naphthoyloxy group and the like), a carbamoylgroup optionally having substituents (e.g., carbamoyl; carbamoyl groupmono- or di-substituted by alkyl group having 1 to 6 carbon atoms suchas methylcarbamoyl, dimethylcarbamoyl group etc., and the like), anamino group optionally having substituents (e.g., amino; amino groupmono- or di-substituted by alkyl group having 1 to 6 carbon atoms suchas methylamino, dimethylamino, ethylamino, diethylamino group etc., andthe like) and the like can be mentioned. The number and the position ofthe substitutions are not particularly limited.

As the ring formed by R₂ and R₃ together with the adjacent nitrogenatom, for example, pyrrolidine, piperidine, homopiperidine, morpholine,piperazine, tetrahydroquinoline, tetrahydroisoquinoline and the like canbe mentioned.

The “hydrocarbon group” of the “hydrocarbon group optionally havingsubstituents” represented by the above-mentioned E, R, R₁ and G may have1 to 5, preferably 1 to 3, the aforementioned substituent atsubstitutable positions of the hydrocarbon group, wherein, when thenumber of substituents is not less than 2, each substituents are thesame or different.

As the “heterocyclic group” of the “heterocyclic group optionally havingsubstituents” represented by the above-mentioned E, R and G, a 5- to12-membered aromatic heterocyclic group and saturated or unsaturatednon-aromatic heterocyclic group containing, as ring-constituting atom(ring atom), 1 to 3 (preferably 1 or 2) kinds of at least 1. (preferably1 to 4, more preferably 1 to 3) hetero atoms selected from oxygen atom,sulfur atom and nitrogen atom and the like can be mentioned. As thementioned above, as the “heterocyclic group” of the “heterocyclic groupoptionally having substituents” represented by G, a saturatedoxygen-containing heterocyclic group containing, as ring atoms, 1 to 4,more preferably 1 to 3, hetero atoms selected from oxygen atom, sulfuratom and nitrogen atom etc., and the like are preferable, particularly a5- to 12-membered saturated oxygen-containing heterocyclic group and thelike are preferable.

As the “aromatic heterocyclic group”, an aromatic monocyclicheterocyclic group, an aromatic fused heterocyclic group and the likecan be mentioned.

As the “aromatic monocyclic heterocyclic group”, for example, a 5- or6-membered aromatic monocyclic heterocyclic group such as furyl,thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc., and thelike can be mentioned.

As the “aromatic fused heterocyclic group”, for example, a 8- to12-membered aromatic fused heterocyclic group (preferably a heterocyclicgroup wherein the aforementioned 5- or 6-membered aromatic monocyclicheterocyclic group is condensed with a benzene ring, or a heterocyclicgroup wherein the same or different two heterocyclic groups of theaforementioned 5- or 6-membered aromatic monocyclic heterocyclic groupare condensed), such as benzofuranyl, isobenzofuranyl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl etc., and the like can be mentioned.

As the “saturated or unsaturated non-aromatic heterocyclic group”, forexample, a 3- to 8-membered (preferably 5- or 6-membered) saturated orunsaturated (preferably saturated) non-aromatic heterocyclic group(aliphatic heterocyclic group) such as oxylanyl, azetidinyl, oxetanyl,thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl,azepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, azocanyl,oxocanyl, thiocanyl, oxazocanyl, thiazocanyl and the like can bementioned. These may be oxo-substituted and examples thereof include2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxazepanyl,2-oxazocanyl, 2-oxotetrahydrofuryl, 2-oxotetrahydropyranyl,2-oxothiolanyl, 2-oxothianyl, 2-oxopiperazinyl, 2-oxooxepanyl,2-oxooxazepanyl, 2-oxothiepanyl, 2-oxothiazepanyl, 2-oxooxocanyl,2-oxothiocanyl, 2-oxooxazocanyl, 2-oxothiazocanyl and the like. A5-membered non-aromatic heterocyclic group such as 2-oxopyrrolidinyl andthe like is preferable.

As the substituent that the “heterocyclic group” of the “heterocyclicgroup optionally having substituents” represented by the above-mentionedE, R and G may have, for example, those similar to the “substituent” ofthe “hydrocarbon group optionally having substituents” represented bythe aforementioned E, R, R₁ and G and the like are used.

The “heterocyclic group” of the “heterocyclic group optionally havingsubstituents” represented by E, R and G may each have 1 to 5, preferably1 to 3, substituents mentioned above at substitutable positions of theheterocyclic group, and when the number of substituents is two or more,the substituents are the same or different.

The bond between R and W in the compound of the present invention isexplained below. When R and W are bonded, the position of the bondbetween R and W is not particularly limited as long as R and W can bebonded. The bondable position of R is the position where the“hydrocarbon group” and “substituent” of the “hydrocarbon groupoptionally having substituents” defined above for R can be bonded, andthe position where the “heterocyclic group” and “substituent” of the“heterocyclic group optionally having substituents” defined above for Rcan be bonded.

As the bondable position of W, a bondable position of the “divalentchain hydrocarbon group” of the “divalent chain hydrocarbon groupoptionally having substituents” defined above for W, a bondable positionof the “divalent chain hydrocarbon group” defined above for W₁ and W₂, abondable position of the “hydrocarbon ring” of the “hydrocarbon ringoptionally having substituents” defined above for ring Z, and a bondableposition of the “heterocyclic group” of the “heterocyclic groupoptionally having substituents” defined above for ring Z can bementioned.

R and W can be bonded at the bondable position thereof and can form aring together with the adjacent nitrogen atom. As such ring, forexample, a saturated nitrogen-containing ring (e.g., azetidine,pyrrolidine, piperidine, homopiperidine etc.), an unsaturatednitrogen-containing ring (e.g., tetrahydropyridine etc.), an aromaticnitrogen-containing ring (e.g., pyrrole etc.), a hetero ring (e.g.,piperazine, morpholine etc.) containing, besides the nitrogen atom towhich R and W are adjacent, at least one hetero atom selected from thegroup consisting of nitrogen, oxygen and sulfur, a fused ring (e.g.,indole, indoline, isoindole, isoindoline, tetrahydroquinoline,tetrahydroisoquinoline etc.) and the like can be mentioned. Of these, a4- to 7-membered ring is preferable.

The ring formed by R and W, which are bonded at each bondable positionthereof, together with the adjacent nitrogen atom may have 1 to 4substituents at substitutable positions thereof. When the number ofsubstituents is 2 or more, the substituents are the same or different.As the substituent, the substituents of the “hydrocarbon groupoptionally having substituents” and “heterocyclic group optionallyhaving substituents” defined for R, and the substituents of the“divalent chain hydrocarbon group optionally having substituents”defined for W can be mentioned. Specifically, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine etc.), a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-ethylpropyl, hexyl etc., and the like can bementioned.

By the bond between R and W, for example,

and the like are formed, but the ring is not limited to these. These mayhave substituents as defined above, and it would be understood for thoseof ordinary skill in the art that they may also have an isomer.

In the present invention, X represents a leaving group, such as ahalogen atom, a benzotriazolyl group, a (2,5-dioxypyrrolidin-1-yl)oxygroup and the like. Of these, a halogen atom such as fluorine, chlorine,bromine, iodine and the like is preferable, and chlorine is particularlypreferable.

In the present invention, M represents a hydrogen atom, a metal cationor a quaternary ammonium ion.

In the present invention, the “metal cation” is exemplified by alkalimetal ion (e.g., Na⁺, K⁺, Li⁺, Cs⁺ and the like), with preference givento Na⁺.

In the present invention, the “quaternary ammonium ion” is exemplifiedby tetramethylammonium ion, tetraethylammonium ion, tetrapropylammoniumion, tetrabutylammonium ion and the like, with preference given totetrabutylammonium ion.

In the compound (II), a pharmacologically acceptable basic salt can beformed between an acidic group in a molecule and an inorganic base or anorganic base etc, and a pharmacologically acceptable acid addition saltcan be formed between a basic group in a molecule and an inorganic acidor an organic acid etc.

Examples of the inorganic basic salt of compound (II) include salt withalkali metal (e.g., sodium, potassium and the like), alkaline earthmetal (e.g., calcium and the like), ammonia etc., and the like, andexamples of the organic basic salt of compound (II) include salt withdimethylamine, triethylamine, piperazine, pyrrolidine, piperidine,2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine,collidine etc., and the like.

Examples of the acid addition salt of compound (II) include inorganicacid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate and thelike), organic acid salt (e.g., acetate, trifluoroacetate, succinate,maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate,methanesulfonate, p-toluenesulfonate and the like) and the like.

The compound (II) of the present invention encompasses hydrates.Examples of the “hydrate” include 0.5 hydrate −5.0 hydrate. Of these,0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferable.

The compound (II) of the present invention encompasses racemates andoptically active compounds. As the optically active compound, suchcompound wherein one enantiomer is in enantiomer excess (e.e.) of notless than 90% is preferable, more preferably in enantiomer excess of notless than 99%.

As an optically active form, an (R)-form represented by the formula:

wherein each symbol is as defined above, is preferable. As thepreferable compounds encompassed in compound (II), for example, thefollowing specific compounds can be mentioned. That is,

-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    trimethylacetate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    cyclohexanecarboxylate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    benzoate,-   2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    benzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    4-methoxybenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    3-chlorobenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    3,4-difluorobenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    4-trifluoromethoxybenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    4-fluorobenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    3,4,5-trimethoxybenzoate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    2-pyridinecarboxylate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    methoxyacetate,-   ethyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   isopropyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   isopropyl    2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   benzyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    tetrahydropyran-4-yl carbonate,-   2-methoxyethyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   2-[ethyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   ethyl    2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    ethyl carbonate,-   2-[[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl    acetate,-   2-[[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl    acetate,-   tert-butyl    [2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]-3-pyridyl]methyl    carbonate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]benzyl    acetate,-   2-[[2-(acetyloxy)ethyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   [(2S)-1-[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]-2-pyrrolidinyl]methyl    acetate,-   ethyl[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]acetate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethyl    benzoate,-   3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propyl    benzoate,-   2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    tetrahydropyran-4-yl carbonate,-   ethyl    2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,    -   ethyl        2-[methyl[[(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl        carbonate,-   ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl    carbonate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl]methyl)amino]ethyl    acetate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](phenyl)amino]ethyl    acetate,-   4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]butyl    acetate,-   ethyl    4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]butyl    carbonate,-   ethyl    3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propyl    carbonate,-   3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propyl    acetate,-   3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propane-1,2-diyl    diacetate,-   diethyl    3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propane-1,2-diyl    biscarbonate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl    3-chlorobenzoate,-   2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   2-ethoxyethyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   3-methoxypropyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    N,N-dimethylglycinate,-   S-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl]thioacetate,-   ethyl    2-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethoxy]ethyl    carbonate,-   ethyl    2-[methyl[[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethoxy]carbonyl]amino]ethyl    carbonate,-   ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    carbonate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl    acetate,-   ethyl    2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    carbonate,-   ethyl    2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    carbonate,-   2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl    acetate,-   2-[[[5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    ethyl carbonate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    1-methylpiperidine-4-carboxylate,-   2-[[4-(aminocarbonyl)phenyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    1-methyl-4-piperidinyl carbonate,-   2-[[4-(aminocarbonyl)phenyl][[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   (−)-ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl]methyl)amino]ethyl    carbonate and-   (+)-ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl    carbonate, a salt thereof and the like can be mentioned.

Of these, the following compounds and salts thereof are preferable.

-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   ethyl    2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    tetrahydropyran-4-yl carbonate,-   2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    tetrahydropyran-4-yl carbonate,-   ethyl    2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    carbonate,-   ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl    carbonate,-   2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl    acetate,-   2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl    acetate,-   ethyl    2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]methyl)amino]ethyl    carbonate,-   ethyl    2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    carbonate,-   ethyl    2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    carbonate, and-   2-[[[5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl    ethyl carbonate.

The compound (II) can be produced by the following method A or B.

(Method A)

The compound (II) or a salt thereof can be obtained by condensation ofcompound (IV) or a salt thereof with compound (V) or a salt thereof inthe presence or absence of a base. The salt of compound (IV) and thesalt of compound (V) here are exemplified by the above-mentioned saltsof compound (II). For example, acid addition salts such as inorganicacid salt (e.g., hydrochloride, sulfate, hydrobromide, phosphate and thelike), organic acid salt (e.g., acetate, trifluoroacetate, succinate,maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate,methanesulfonate, p-toluenesulfonate and the like), and the like can bementioned.

wherein each symbol is as defined above. The reaction of Method A isgenerally conducted in a solvent, and a solvent that does not inhibitthe reaction of Method A is selected as appropriate. Examples of suchsolvent include ethers (e.g., dioxane, tetrahydrofuran, diethyl ether,tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethylether and the like), esters (e.g., ethyl formate, ethyl acetate, butylacetate and the like), halogenated hydrocarbons (e.g., dichloromethane,chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane and thelike), hydrocarbons (e.g., n-hexane, benzene, toluene and the like),amides (e.g., formamide, N,N-dimethylformamide, N,N-dimethylacetamideand the like), ketones (e.g., acetone, methyl ethyl ketone, methylisobutyl ketone and the like), nitriles (e.g., acetonitrile,propionitrile and the like) and the like, as well as dimethyl sulfoxide,sulfolane, hexamethylphosphoramide, water and the like, which may beused alone or as a mixed solvent. The amount of the solvent to be usedis not particularly limited as long as the reaction mixture can bestirred, which is generally 2- to 100-fold amount by weight, preferably5- to 50-fold amount by weight, relative to 1 mole of compound (IV) or asalt thereof.

The amount of compound (IV) or a salt thereof to be used is generally1-10 mole, preferably 1-3 mole, relative to 1 mole of compound (IV) or asalt thereof. The reaction of Method A is carried out within atemperature range of from about 0° C. to 100° C., preferably 20° C. to80° C.

The reaction time of Method A varies depending on the kind of compounds(IV), (V) or a salt thereof and solvent, reaction temperature and thelike, but it is generally 1 min. −96 hrs., preferably 1 min. −72 hrs.,more preferably 15 min. −24 hrs.

The base in Method A is, for example, an inorganic base (e.g., sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydrogencarbonate etc.), a tertiary amine (e.g., triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, 4-dimethylaminopyridine and the like); alkyleneoxides (e.g., propylene oxide, epichlorohydrin etc.) and the like. Theamount of the base to be used is generally 1 mole −10 mole, preferably 1mole −3 mole, relative to 1 mole of compound (V) or a salt thereof.

The compound (IV) or a salt thereof can be produced according to themethod described in JP-A-61-50978, U.S. Pat. No. 4,628,098 and the likeor a method similar thereto.

The compound (V) or a salt thereof can be produced according to a methodknown per se or a method analogous thereto. For example, when X is achlorine atom, compound (V) can be obtained by reacting a compoundrepresented by the formula (VII):

wherein each symbol is as defined above, or a salt thereof withphosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate,thiophosgene and the like in the presence of an acid scavenger in asolvent (e.g., tetrahydrofuran, acetonitrile, dichloromethane etc.).Alternatively, compound (V) can be also obtained by treatingethylcarbamate, which is obtained by reacting compound (VII) or a saltthereof with ethyl chloroformate, with phosphorus oxychloride accordingto the method described in Synthetic Communications, vol. 17, p. 1887(1987) or a method analogous thereto. As the salt of compound (VII), forexample, acid addition salts such as inorganic acid salts (e.g.,hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acidsalts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate,propionate, citrate, tartrate, lactate, oxalate, methanesulfonate,p-toluenesulfonate etc.), and the like can be mentioned.

As the acid scavenger used here, for example, inorganic bases (e.g.,sodium carbonate, potassium carbonate, calcium carbonate, sodiumhydrogen carbonate etc.), tertiary amine (e.g., triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine,lutidine, γ-collidine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine etc.)and the like can be mentioned. The compound (VII) and a salt thereof canbe produced according to a method known per se or a method analogousthereto. For example, when D₁ is other than a bond, compound (VII) canbe obtained by condensing a compound represented by the formula (VIII):

wherein R₄ is a hydrogen atom or nitrogen-protecting group, and othersymbols are as defined above, or a salt thereof with carboxylic acid orthionic acid represented by the formula (IX):

wherein each symbol is as defined above, or a reactive derivativethereof (e.g., anhydride, halide etc.), or a salt thereof in a suitablesolvent (e.g., ethyl acetate, tetrahydrofuran, dichloromethane,N,N-dimethylformamide etc., followed by deprotection as necessary. Asthe salt of compound (VIII), for example, acid addition salts such asinorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide,phosphate etc.), organic acid salts (e.g., acetate, trifluoroacetate,succinate, maleate, fumarate, propionate, citrate, tartrate, lactate,oxalate, methanesulfonate, p-toluenesulfonate etc.) etc., and the likecan be mentioned.

Alternatively, when D₁ is a bond, compound (VII) can be obtained bycondensing carboxylic acid or thionic acid represented by the formula(X):

wherein each symbol is as defined above, or a reactive derivativethereof (e.g., anhydride, halide etc.), or a salt thereof with acompound represented by G-D₂-H in a suitable solvent (e.g., ethylacetate, tetrahydrofuran, dichloromethane, N,N-dimethylformamide etc.),followed by deprotection, as necessary. As the salt of compound (X), forexample, acid addition salts such as inorganic acid salts (e.g.,hydrochloride, sulfate, hydrobromide, phosphate etc.), organic acidsalts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate,propionate, citrate, tartrate, lactate, oxalate, methanesulfonate,p-toluenesulfonate etc.) and the like, salts with alkali metal (e.g.,sodium, potassium etc.), alkaline earth metal (e.g., calcium etc.),ammonia etc., and the like, and for example, organic base such asdimethylamine, triethylamine, piperazine, pyrrolidine, piperidine,2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine,collidine etc., and the like can be mentioned.

As the protecting group represented by R₄ in the formula (VIII) and theformula (X), for example, a formyl group, a C₁₋₆ alkyl-carbonyl group(e.g., acetyl, ethylcarbonyl etc.), a benzyl group, atert-butyloxycarbonyl group, a benzyloxycarbonyl group, anallyloxycarbonyl group, a C₇₋₁₀ aralkyl-carbonyl group (e.g.,benzylcarbonyl etc.), a trityl group and the like are used. These groupsmay be substituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine etc.), a nitro group and the like.

As a method for removing such protecting groups, a method known per seor a method analogous thereto is used, which is, for example, a methodusing an acid, a base, reduction, UV light, palladium acetate etc., andthe like are used.

(Method B)

The compound (II) and a salt thereof can be obtained by subjectingcompound (VI) or a salt thereof to oxidization reaction.

wherein each symbol is as defined above.

The reaction in Method B can be carried out using an oxidant such asnitric acid, hydrogen peroxide, peroxyacid, peroxyacid ester, ozone,dinitrogen tetraoxide, iodosobenzene, N-halosuccinimide,1-chlorobenzotriazole, tert-butyl hypochlorite,diazabicyclo[2.2.2]octane-bromine complex, sodium metaperiodate,selenium dioxide, manganese dioxide, chromic acid, cerium ammoniumnitrate, bromine, chlorine, sulfuryl chloride, magnesiummonoperoxyphthalate and the like. The amount of the oxidant to be usedis generally 0.5 mole −2 mole, preferably 0.8 mole −1.2 mole, per 1 moleof compound (VI) or a salt thereof. The oxidization may be carried outusing the above-mentioned oxidant such as hydrogen peroxide andperoxyacids in the presence of a catalyst such as vanadium acetate,vanadium oxide acetylacetonate, titanium tetraisopropoxide and the like.

The reaction of Method B is generally carried out in a solvent inert tothe above-mentioned oxidation reaction. Examples of the “inert solvent”include water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanoletc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles(e.g., acetonitrile, propionitrile etc.), amides (e.g., formamide,N,N-dimethylformamide etc.), ethers (e.g., diethyl ether, tert-butylmethyl ether, diisopropyl ether, dioxane, tetrahydrofuran etc.),sulfoxides (e.g., dimethyl sulfoxide etc.) and polar solvents (e.g.,sulfolane, hexamethylphosphoramide etc.), which may be used alone or asa mixed solvent thereof. The “inert solvent” is used in generally 1- to100-fold amount by weight of compound (VI) or a salt thereof.

The reaction temperature is generally from −80° C. to 80° C., preferablyfrom 0° C. to 30° C.

The reaction time is generally 1 min. −6 hrs., preferably 15 mins. −1hr.

The compound (VI), which is a starting material in Method B, can beobtained by a reaction similar to that in Method A, by the use of, forexample, a compound represented by the following formula (XI):

wherein each symbol is as defined above, instead of compound (IV).

The compound (XI) can be synthesized according to the methods describedin the following references or a method analogous thereto:JP-A-61-50978, JP-A-54-141783, JP-A-61-22079, JP-A-1-6270,JP-A-63-146882.

The salt of compound (VI) is exemplified by the above-mentioned salts ofthe compound (II), which are acid addition salts such as inorganic acidsalt (e.g., hydrochloride, sulfate, hydrobromide, phosphate and thelike), organic acid salt (e.g., acetate, trifluoroacetate, succinate,maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate,methanesulfonate, p-toluenesulfonate and the like) and the like.

The compound (II) or a salt thereof obtained by the above-mentionedmethods A or B can be isolated and purified from the reaction mixture bya separation means known per se (e.g., concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like). Sincecompound (II) and a salt thereof obtained by the above-mentioned methodsA or B encompass any isomers thereof, optically pure compound (II) and asalt thereof can be obtained by, for example, subjecting compound (II)or a salt thereof to optical resolution, or asymmetric oxidation ofcompound (VI) or a salt thereof.

The method of optical resolution includes methods known per se, such asa fractional recrystallization method, a chiral column method, adiastereomer method, and so forth. Asymmetric oxidation includes methodsknown per se, such as the method described in WO96/02535 and the like.

The “fractional recrystallization method” includes a method in which asalt is formed between a racemate and an optically active compound[e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine, etc.], which salt is separated byfractional recrystallization etc., and, if desired, subjected to aneutralization process to give a free optical isomer.

The “chiral column method” includes a method in which a racemate or asalt thereof is applied to a column for optical isomer separation(chiral column). In the case of liquid chromatography, for example,optical isomers are separated by adding a racemate to a chiral columnsuch as ENANTIO-OVM (produced by Tosoh Corporation), the DAICEL CHIRALseries (produced by Daicel Corporation) and the like, and developing theracemate in water, a buffer (e.g., phosphate buffer), an organic solvent(e.g., hexane, ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine, triethylamine, etc.), or a solventmixture thereof. In the case of gas chromatography, for example, achiral column such as CP-Chirasil-DeX CB (produced by GL Science) andthe like is used to separate optical isomers.

The “diastereomer method” includes a method in which a racemate and anoptically active reagent are reacted to give a diastereomeric mixture,which is then subjected to ordinary separation means (e.g., fractionalrecrystallization, chromatography, etc.) to obtain either diastereomer,which is subjected to a chemical reaction (e.g., acid hydrolysis, basehydrolysis, hydrogenolysis, etc.) to cut off the optically activereagent moiety, whereby the desired optical isomer is obtained. Said“optically active reagent” includes, for example, optically activeorganic acids such as MTPA [α-methoxy-α-(trifluoromethyl)phenylaceticacid], (−)-menthoxyacetic acid and the like, optically activealkoxymethyl halides such as(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane etc.,and the like.

Further, a benzimidazole compound represented by the following generalformula (III) or a salt thereof is also mentioned as the specificexample of the above-mentioned prodrug.

In the above-mentioned formula (III), D indicates an oxygen atom or abond, and Q indicates a hydrocarbon group optionally having asubstituent group.

The “hydrocarbon group” of the “hydrocarbon group optionally having asubstituent group” represented by Q includes an aliphatic or aromatichydrocarbon group, and an aliphatic hydrocarbon group mentioned heremeans a saturated or unsaturated, linear, branched or cyclic hydrocarbongroup. The hydrocarbon group is preferably a hydrocarbon group having 1to 14 carbon atoms, and for example, a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₂₋₆ alkynyl group, a C₃₋₈ cycloalkyl group and a C₆₋₁₄ arylgroup are exemplified. A C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group and aC₆₋₁₄ aryl group are preferred, and above all a C₁₋₆ alkyl group and aC₃₋₈ cycloalkyl group are more preferred.

The above-mentioned “alkyl group” is a linear or branched alkyl group,preferably an alkyl group having 1 to 6 carbon atoms (“C₁₋₆ alkylgroup”) and for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and the like areexemplified. An alkyl group having 1 to 4 carbon atoms is preferred.Among these, in Q, methyl, ethyl, isopropyl and tert-butyl arepreferred, and tert-butyl is preferred particularly.

The above-mentioned “C₂₋₆ alkenyl group” is a linear or branched alkenylgroup having 2 to 6 carbon atoms. Example thereof includes vinyl,n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl,tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, 1-methylpropenyl,n-hexenyl, isohexenyl, 1,1-dimethylbutenyl, 2,2-dimethylbutenyl,3,3-dimethylbutenyl, 3,3-dimethylpropenyl, 2-ethylbutenyl and the like.An alkenyl group having 2 to 4 carbon atoms is preferred and vinyl,n-propenyl and isopropenyl are preferred particularly.

The above-mentioned “C₂₋₆ alkinyl group” is a linear or branched alkinylgroup having 2 to 6 carbon atoms. Example thereof includes ethynyl,n-propynyl (1-propynyl), isopropynyl (2-propynyl), n-butynyl,isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, isopentynyl,neopentynyl, 1-methylpropynyl, n-hexynyl, isohexynyl,1,1-dimethylbutynyl, 2,2-dimethylbutynyl, 3,3-dimethylbutynyl,3,3-dimethylpropynyl, 2-ethylbutynyl and the like. An alkynyl grouphaving 2 to 3 carbon atoms is preferred and ethynyl, 1-propynyl and2-propynyl are preferred particularly.

The above-mentioned “C₃₋₈ cycloalkyl group” is a cycloalkyl group having3 to 8 carbon atoms. Example thereof includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Acycloalkyl group having 5 to 7 carbon atoms is preferred and among them,cyclopentyl, cyclohexyl and cycloheptyl are preferred. Cyclohexyl ispreferred particularly.

The above-mentioned “aryl group” is a monocyclic or condensed polycyclicaromatic hydrocarbon group, and preferably an aromatic hydrocarbon grouphaving 6 to 14 carbon atoms (“C₆₋₁₄ aryl group”). Example thereofincludes phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl. Anaromatic hydrocarbon group having 6 to 10 carbon atoms is preferred, andphenyl is particularly preferred in Q.

The above-mentioned “hydrocarbon group” may be substituted, and examplesof the substituent group include, for example, a C₆₋₁₄ aryl group, ahydroxyl group, a halogen, an optionally halogenated C₁₋₆ alkoxy group,a C₇₋₁₂ aralkyloxy group, a C₁₋₅ alkoxy-carbonyl group, an optionallyhalogenated C₁₋₆ alkyl group, an amino group which may be substitutedwith a C₁₋₆ alkyl group, and the like.

Examples of the substituent group in the “alkyl group optionally havinga substituent group” include, for example, an aryl group, a hydroxylgroup, a halogen, an alkoxy group which may be substituted with 1 to 5halogens, a C₇₋₁₂ aralkyloxy group, a C₁₋₅ alkoxy-carbonyl group, andthe like. The number of said substituent group is 1 to 5 and preferably1 to 3.

Examples of the substituent group in the “aryl group optionally having asubstituent group” include a halogen, an alkyl group which may besubstituted with 1 to 5 halogens, an aryl group, a hydroxyl group, analkoxy group aralkyloxy group, a C₁₋₅ alkoxy-carbonyl group, and thelike. The number of said substituent group is 1 to 5 and preferably 1 to3.

The above-mentioned “C₁₋₆ alkyl group”, “C₂₋₆ alkenyl group” and “C₂₋₆alkinyl group” may be substituted, and examples of the substituent groupinclude (i) a C₆₋₁₄ aryl group, (ii) a hydroxyl group, (iii) a halogen,(iv) an optionally halogenated C₁₋₆ alkoxy group, (v) a C₇₋₁₂ aralkyloxygroup, (vi) a C₁₋₅ alkoxy-carbonyl group, (vii) an acylamino group,(viii) an amino group which may be substituted with a C₁₋₆ alkyl group,and the like, and among these, (i) to (vii) are preferred. The number ofsaid substituent group is 1 to 5 and preferably 1 to 3.

The above-mentioned “C₃₋₈ cycloalkyl group” and “C₆₋₁₄ aryl group” maybe substituted, and examples of the substituent group include (i) aC₆₋₁₄ aryl group, (ii) a hydroxyl group, (iii) a halogen, (iv) anoptionally halogenated C₁₋₆ alkoxy group, (v) a C₇₋₁₂ aralkyloxy group,(vi) a C₁₋₅ alkoxy-carbonyl group, (vii) a C₁₋₆ alkyl group which may besubstituted with halogen, (viii) an amino group which may be substitutedwith a C₁₋₆ alkyl group, and the like, and among these, (i) to (vii) arepreferred particularly. The number of said substituent group is 1 to 5and preferably 1 to 3.

In the formula (III), Q is preferably a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup and a C₂₋₆ alkinyl group, which may have a substituent groupselected from a group consisting of (i) a C₆₋₁₄ aryl group, (ii) ahydroxyl group, (iii) a halogen, (iv) an optionally halogenated C₁₋₆alkoxy group, (v) a C₇₋₁₂ aralkyloxy group, (vi) a C₁₋₆ alkoxy-carbonylgroup and (vii) an acylamino group, or a C₃₋₈ cycloalkyl group or aC₆₋₁₄ aryl group, which may have a substituent selected from the groupconsisting of (i) a C₆₋₁₄ aryl group, (ii) a hydroxyl group, (iii) ahalogen, (iv) an optionally halogenated C₁₋₆ alkoxy group, (v) a C₇₋₁₂aralkyloxy group, (vi) a C₁₋₅ alkoxy-carbonyl group, and (vii) anoptionally halogenated C₁₋₆ alkyl group.

Q is more preferably (1) a C₁₋₆ alkyl group which may have 1 to 5substituent groups selected from the group consisting of (i) a C₆₋₁₄aryl group, (ii) a hydroxyl group, (iii) a halogen, (iv) a C₁₋₆ alkoxygroup which may be substituted with 1 to 5 halogens, (v) a C₇₋₁₂aralkyloxy group and (vi) a C₁₋₆ alkoxy-carbonyl group, or (2) a C₆₋₁₄aryl group which may have 1 to 5 substituent groups selected from thegroup consisting of (i) a halogen, (ii) a C₁₋₆ alkyl group which may besubstituted with 1 to 5 halogens, (iii) a C₆₋₁₄ aryl group, (iv) ahydroxyl group, (v) a C₁₋₆ alkoxy group which may be substituted with 1to 5 halogens, (vi) a C₇₋₁₂ aralkyloxy group and (vii) a C₁₋₅alkoxy-carbonyl group.

Q is further more preferably a C₁₋₆ alkyl group which may have asubstituent group selected from the group consisting of (i) a C₆₋₁₄ arylgroup, (ii) a hydroxyl group, (iii) a halogen, (iv) an optionallyhalogenated C₁₋₆ alkoxy group, (v) a C₇₋₁₂ aralkyloxy group, (vi) a C₁₋₅alkoxy-carbonyl group and (vii) an acylamino group; or a C₃₋₈ cycloalkylgroup or a C₆₋₁₄ aryl group, which may have a substituent group selectedfrom the group consisting of (i) a C₆₋₁₄ aryl group, (ii) a hydroxylgroup, (iii) a halogen, (iv) an optionally halogenated C₁₋₆ alkoxygroup, (v) a C₇₋₁₂ aralkyloxy group, (vi) a C₁₋₅ alkoxy-carbonyl groupand (vii) an optionally halogenated C₁₋₆ alkyl group.

Among these, Q is preferably a C₁₋₆ alkyl group which may be substitutedwith a C₆₋₁₄ aryl group or a C₆₋₁₄ aryl group, and Q is preferablyphenyl group, methyl or tert-butyl group in particular.

In compound (III), an acidic group in the molecule can form apharmacologically acceptable base salt with an inorganic salt or anorganic salt or the like, and a basic group in the molecule can form apharmacologically acceptable acid additive salt with an inorganic saltor an organic salt or the like.

One preferable form of compound (III) of the present invention includesa compound wherein D is a bond and Q is an alkyl group optionally havinga substituent group or an aryl group optionally having a substituentgroup.

Examples of the inorganic base salt of compound (III) include, forexample, salts with an alkali metal (for example, sodium, potassium andthe like), an alkali earth metal (for example, calcium and the like),ammonia and the like, and Examples of the organic base salt of compound(III) include, for example, salts with dimethylamine, triethylamine,piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine,ethanolamine, diethanolamine, pyridine, collidine and the like.

The acid additive salt of compound (III) includes, for example,inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide,phosphate and the like), organic acid salts (for example, acetate,trifluoroacetate, succinate, maleate, fumarate, propionate, citrate,tartarate, lactate, oxalate, methanesulfoante, p-toluenesulfoante, andthe like), etc.

The compound (III) of the present invention includes a hydrate. Said“hydrate” includes a 0.5 hydrate to 5.0 hydrates. Among these, 0.5hydrate, 1.0 hydrate, 1.5 hydrates and 2.0 hydrates are preferred.

The compound (III) of the present invention includes a racemic compoundand an optically active compound. As the optically active compound, suchcompound wherein one enantiomer is in enantiomer excess (e.e.) of notless than 90% is preferable, more preferably in enantiomer excess of notless than 99%. As an optically active form, an (R)-isomer represented bythe formula:

wherein each symbol is as defined above, is preferable.

The compound (III) can be produced by known methods per se, and areproduced by the methods disclosed in, for example, JP-A 2002-187890, WO02/30920 and the like, or analogous methods thereto. Further, theoptically active compound (III) can be obtained by optical resolutionmethods (a fractional recrystallization method, a chiral column method,a diastereomer method, a method using microorganism or enzyme, and thelike) and an asymmetric oxidation method, etc. As the PPI of otherbenzimidazole derivative, the present invention can be applied to thecompound disclosed in WO 03/27098.

Although the compounding amounts of the active ingredient represented bythe general formulae (I′), (I), (II) and (III) used in the presentinvention differ depending on the kinds and doses of the activeingredient, the amounts are, for example, about 1% by weight to about60% by weight based on the total amount of tablets or granules of thepresent invention, preferably about 1% by weight to about 50% by weightand further preferably about 8% by weight to about 40% by weight. Whenthe active ingredient is a benzimidazole compound PPI, in particularlansoprazole, the amount is about 8% by weight to about 40% by weight.

In case of capsules containing the imidazole PPI, especiallybenzimidazole PPI represented by the general formula (I′) or (I) such aslansoprazole or an optically active compound thereof (R-isomer and thelike) and the imidazole derivative PPI represented by the formula (II)and (III), 2 kinds or more of a tablet, granule or fine granule havingdifferent behavior of release (for example, 2 kinds of granules such asgranules wherein the active ingredient is released comparatively quicklyand granules wherein the active ingredient is released with prolongedtime) may be filled in combination, using release-controlledcoating-layers which have different release properties and conditionsrespectively. Further, 2 kinds of these release-controlledcoating-layers may be stacked in 2 or more layers in the respectivegranules or fine granules. The preparation which enhances blood levelsat a more earlier stage after administration to reveal drug efficacy andthen sustain the drug efficacy by the expression of the drug efficacy ofthe release-controlled granule can be provided, by preparing apreparation (preferably a capsule) which contains a granule having anintermediate layer on the core particle containing the above-mentionedactive ingredient and only one layer of enteric coat on saidintermediate layer (accordingly, among the above-mentionedrelease-controlled granule or fine granule by the present invention, thegranule in which the release of active ingredient is comparativelyrapid), in addition to a tablet, granule or fine granule having therelease-controlled coating-layers of the present invention and thedigestive tract retentive gel-forming polymer; or by administeringcapsules containing a tablet, granule or fine granule having the releasecontrol layer of the present invention and the digestive tract retentivegel-forming polymer, together with a preparation containing onlygranules having a usual enteric coat. Further, when the tablet (in thiscase, small size tablet is preferable); granule or fine granule to befilled has an enough release-controlling function, the capsules of thepresent invention may not always contain the gel-forming polymer.Capsules may be prepared using only the release-controlled tablet,granule or fine granule, or by combining the release-controlled tablet,granule or fine granule with a fast-releasing type granule having onlyenteric coat. In case of such combined preparations and combinedadministration, there can be prepared the preparations by which theblood level is preferably enhanced at a more earlier stage to achievedrug efficacy and to reach the first maximal blood level, and then thesecond maximal blood level is reached by the release of activeingredient from granules in which the release was controlled, that is,two peaks are expressed. Further, the controlled release preparationsuch as the above-mentioned controlled release capsule of the presentinvention and a usual capsule wherein the active ingredient iscomparatively released quickly may be administered at the same time orat an interval. A high blood level of active ingredient can bemaintained over a long time by such combined administration.

Usual enteric-coated Granules can be produced, for example, according tothe method described in JP-A 63-301826. Further, it is preferable toprepare a stabilized preparation according to the method described inJP-A 62-277322.

Further, the granule which contains lansoprazole or optically activeform thereof and the like at a higher concentration and is sufficientlystabilized can be produced as follow. Namely, there are produced thegranules having an active ingredient layer, an intermediate layer formedon said active ingredient layer and an enteric coated layer formed onsaid intermediate layer, wherein said active ingredient layer containsabout 10% by weight to about 40% by weight of lansoprazole and the likebased on the total amount of the granule and a basic inorganic salt as astabilizer and average particle diameter is about 600 μm to about 2500μm, using known granulation methods such as a fluid-bed granulationmethod (for example, a centrifugal fluid-bed granulation method), afluidized granulation method and a stirring granulation method (forexample, a fluid-bed fluidized granulation method).

Specifically, the active ingredient layer can be obtained, for example,by coating a core particle with a dusting powder containing theimidazole PPI, a basic metal salt, an excipient, a disintegrant and thelike while spraying a binding solution such as hydroxypropylcelluloseand the like on the core particle. As said core particle, for example,Nonpareil prepared by coating sucrose (75 parts by weight) with cornstarch (25 parts by weight) by a known method per se, a spherical coregranule using crystalline cellulose and the like are exemplified.Further, a core granule itself may be the above-mentioned activeingredient of drug. The average particle size of said granules is 14 to80 mesh in general.

As the core, a spherically granulated product of sucrose and starch, aspherically granulated product of crystalline cellulose, a sphericallygranulated product of crystalline cellulose and lactose and the like areexemplified.

The ratio of coating layer relative to the core can be selected within arange of being able to control the elution property of active ingredientand the particle size of granules. For example, it is usually about 0.2part by weight to about 5 parts by weight based on 1 part by weight ofcore, and preferably about 0.1 part by weight to about 5 parts byweight.

Then, the intermediate layer is formed on the active ingredient layerobtained by a conventional method. For example, the component of theintermediate layer is diluted with purified water and the like, and themixture is sprayed in liquid form to coat the active ingredient layer.At this time, it is preferable to coat the layer while spraying abinding agent such as hydroxypropylcellulose. Examples of theintermediate layer include, for example, a layer in which sugars such assucrose (purified white sugar (those pulverized (powder sugar) and thosenot pulverized) and the like), starch sugar such as corn starch,lactose, honey and sugar alcohol (D-mannitol, erythritol and the like)are appropriately compounded with polymeric base materials such as lowsubstituted hydroxypropylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose (for example, TC-5 and the like),polyvinyl pyrrolidone, polyvinyl alcohol, methylcellulose andhydroxyethyl methylcellulose. Excipients (for example, masking agent(titanium oxide and the like)) and antistatic agents (titanium oxide,talc and the like) which are added to prepare a preparation may befurther appropriately added in the intermediate coating layer, ifnecessary.

The coat amount of the intermediate coating layer is usually, forexample, about 0.02 part by weight to about 1.5 parts by weight based on1 part by weight of granules containing the benzimidazole PPI, andpreferably about 0.05 part by weight to about 1 part by weight.

Further, the granules which contain lansoprazole and the like at a highconcentration and are sufficiently stabilized can be produced by forminga enteric coated layer on the intermediate coating layer by aconventional method. As the component of the enteric coated layer, forexample, sustained release base materials such as aqueous entericpolymer base materials such as cellulose acetate phthalate (CAP),hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, ethyl acrylate-methyl methacrylate-trimethylammoniumethylmethacrylate chloride copolymer (Eudragit RS or RL; manufactured by RohmCo.), methyl methacrylate-ethyl acrylate copolymer (Eudragit NE30D;manufactured by Rohm Co.), carboxymethyl ethylcellulose and shellac;plasticizers such as water-soluble polymer, triethyl citrate,polyethylene glycol (polyethylene glycol 6000 (trade name: Macrogol6000, and the like), acetylated monoglyceride, triacetin and castor oilare used. These may be used alone or by mixing 2 kinds or more.

The coat amount of the enteric coated layer is about 10% by weight toabout 70% by weight based on the total amount of granules before entericcoating, preferably about 10% by weight to about 50% by weight and morepreferably about 15% by weight to about 30% by weight.

In case of a tablet, for example, the benzimidazole compound, anexcipient, a binding agent, a disintegrant, a lubricant and the like aremixed to directly produce tables by compression, or the granules whichis produced in same manner as the above-mentioned granules can becompressed into tablet. Further, alternatively, 2 layered tablets may beprepared with a commercially available multilayer tablet machine usingthe granulated granules.

Among the preparations of the present invention, preparations containingthe PPI of benzimidazole compound represented by the general formula(I′) such as lansoprazole and optically active form thereof, above allbenzimidazole PPI compound represented by the general formula (I), andthe PPI of a prodrug-type imidazole compound derivative (in particular,a compound represented by the above-mentioned general formula (II) and(III) and an optically active compound thereof) have superior anti-ulcereffect, gastric juice secretion suppressing effect, mucosa protectiveeffect, anti-Helicobacter pylori effect and the like in vivo, and areuseful as a medicine because of low toxicity. In particular, since theimidazole compound represented by the above-mentioned general formula(II) is stable to an acid, it is unnecessary to prepare an entericpreparation for oral administration, the cost of preparing entericpreparations is reduced, and the patients with weak deglutition, inparticular, aged people and children are easily dosed because the sizeof the preparations becomes small. Further, since the absorption isfaster than enteric preparations, gastric juice secretion suppressingeffect is rapidly expressed, and since it is gradually converted to itsoriginal compound in vivo, it has a sustainability and is useful asanti-ulcer agents and the like. The PPI compound of compound (I′) of thepresent invention or a salt thereof is less toxic, and can be orally orparenterally (for example, local, rectal, vein administration) andsafely administered as it is or as a pharmaceutical composition bymixing with a pharmacologically acceptable carrier according to a knownmethod per se, that is, for example, as a preparation such as a tablet(including sugar coated tablet and film coated tablet), powder, granule,capsule (including soft capsule), intraoral disintegrating tablet,liquid, injection, suppository, sustained-release agent and liniment.

The tablet, granule or fine granule of the present invention can beorally administrated to mammals (for example, human, monkey, sheep,horse, dog, cat, rabbit, mouse and the like) for the treatment andprevention of digestive ulcer (for example, gastric ulcer, duodenumulcer, marginal ulcer and the like), Zollinger-Ellison syndrome,gastritis, reflux esophagitis, Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD) with no esophagitis, NUD (Non UlcerDyspepsia), gastric cancer (including gastric cancer accompanied withthe production promotion of interleukin-1β caused by gene polymorphismof interleukin-1), gastric MALT lymphoma and the like; the eradicationof Helicobacter pylori, the suppression of upper digestive tracthemorrhage caused by the digestive ulcer, acute stress ulcer andhemorrhagic gastritis; the suppression of upper digestive tracthemorrhage caused by invasive stress (stress caused by major operationwhich requires intensive management after operation and bycerebro-vascular accident, head lesion, multiorgan disorder and widerange burn which require intensive care), and the treatment andprevention of ulcer caused by non steroid anti-inflammatories; thetreatment and prevention of hyperchylia and ulcers caused by stressafter operation, etc. The granules and capsules of the present inventionmay be used in combination with other active ingredients (for example, 1to 3 active ingredients) for the eradication of Helicobacter pylori andthe like.

Examples of the “other active ingredients” include, for example, anantibacterial such as an anti-Helicobacter pylori active substance, animidazole compound and a quinolone compound, and bismuth salts. Inparticular, pharmaceuticals obtained by combining the granules andcapsules of the present invention with the antibacterials arepreferable. Among these, the combination with an antibacterial such asan anti-Helicobacter pylori active substance and an imidazole compoundis preferable. Examples of the anti-Helicobacter pylori active substanceinclude, for example, penicillin antibiotic (for example, amoxicillin,benzylpenicillin, piperacillin, mecillinam and the like), cephemantibiotic (for example, cefixime, cephachlor and the like), macrolideantibiotic (for example, erythromycin antibiotic such as erythromycinand clarithromycin), tetracycline antibiotic (for example, tetracycline,minocycline, streptomycin and the like), aminoglycoside antibiotic (forexample, gentamicin, amikacin and the like), imipenem etc. Inparticular, penicillin antibiotic, macrolide antibiotic and the like arepreferred.

Examples of the “imidazole compound” include, for example,metronidazole, miconazole and the like. Examples of the “bismuth salt”include, for example, there are mentioned bismuth acetate, bismuthcitrate and the like. The antibacterial of “quinolone compound” is alsopreferable, and for example, ofloxacin, ciproxacin and the like areexemplified. In particular, it is preferable to use the granules andcapsules of the present invention together with penicillin antibiotic(for example, amoxicillin and the like) and/or erythromycin antibiotic(for example, clarithromycin and the like) for the eradication ofHelicobacter pylori.

Further, for example, in case of lansoprazole, capsules containing 15 mgof crystalline lansoprazole have been often filled in No. 3 capsules,and capsules containing 30 mg have been often filled in No. 1 capsules.However, the granules containing an active ingredient at highconcentration are unexpectedly obtained by providing an intermediatecoating layer, compounding a basic inorganic salt stabilizer and furthercontrolling the particle size of granules without damaging the stabilityof the active ingredient and preparation. Thus, since the amount ofcomponents other than the active ingredient can be reduced, capsulescontaining 15 mg can be miniaturized to No. 4 to No. 5 capsules andcapsules containing 30 mg can be miniaturized to No. 3 to No. 5capsules.

Further, No. 1 to No. 3 capsule can be also used for the capsulecontaining 60 mg.

Further, in case of the optically active compound of lansoprazole, No. 3to No. 5 capsule, No. 2 to No. 4 capsule and No. 1 to No. 3 capsule canbe used for the capsule containing 30 mg, 40 mg and 60 mg respectively.

For example, since the capsule containing 60 mg of lansoprazole orlansoprazole R-isomer contains the active ingredient at highconcentration and the capsule is miniaturized, it is easy to take andsuitable for treatment of acid excessive secretion symptom includingZollinger-Ellison syndrome in particular.

Dose per day differs depending on the extent of symptom, age foradministration objective, sexuality, body weight, timing ofadministration, interval, the kind of active ingredient and the like,and are not specifically limited. For example, when the drug is orallyadministrated to adults (60 kg) as an anti-ulcer agent, the dose isabout 0.5 to 1500 mg/day and preferably about 5 to 150 mg/day as activeingredient. These preparations containing these benzimidazole orimidazole compound may be divided to administer once a day or 2 to 3times a day.

Further, the form of package may be also stabilized in order to improvethe stability of the solid preparation of the present invention atstorage or transportation. For example, the stabilization of the capsulepreparation containing the benzimidazole or imidazole compound of thepresent invention can be improved by using package form such as packagesuppressing the permeation of oxygen and moisture, package replaced withgas (namely, package replaced with gas other than oxygen), vacuumpackage and package enclosed with a deoxidizer. The stabilization isimproved by reducing oxygen amount with which the solid preparation isdirectly brought in contact, using these package forms. When adeoxidizer is enclosed, the pharmaceutical solid preparation is packedwith an oxygen permeating material, and then another packing may becarried out together with the package.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Synthetic Examples, Examples andExperiment Examples. The present invention is not limited by theExamples.

The corn starch, hydroxypropyl cellulose (HPC-L), polyethylene glycol6000 and titanium oxide used in the following Examples of Preparationare the conformed materials to the 14th revised Japanese Pharmacopoeia.

In the following Reference Examples and Synthetic Examples, roomtemperature means about 15-30° C.

¹H-NMR spectra were determined with CDCl₃, DMSO-d₆ and CD₃OD as thesolvent using Varian Gemini-200 and Mercury-300; data are shown inchemical shift δ (ppm) from the internal standard tetramethylsilane.

Other symbols in the present specification mean the following.

s: singlet

d: doublet

t: triplet

q: quartet

m: multiplet

br: broad

bs: broad singlet

bm: broad multiplet

J: coupling constant

Reference Example 1 tert-Butyl 2-hydroxyethyl(methyl)carbamate

To a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90mL) was dropwise added a mixture of di-tert-butyl dicarbonate (87.30 g)and ethyl acetate (10 mL) under ice-cooling. After stirring at roomtemperature for 2 hrs., the mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (150 mL), washedwith water (100 mL) and dried over anhydrous magnesium sulfate.Concentration under reduced pressure gave the title compound (66.19 g)as a colorless oil.

¹H-NMR(CDCl₃): 1.47 (9H, s), 2.92 (3H, s), 3.40 (2H, t, J=5.1 Hz),3.72-3.80 (2H, m).

Reference Example 2 2-(Methylamino)ethyl acetate hydrochloride

To a mixture of 2-(methylamino)ethanol (1.50 g) and ethyl acetate (20mL) was added di-tert-butyl dicarbonate (4.37 g) under ice-cooling.After stirring under ice-cooling for 1.5 hrs., acetic anhydride (2.08mL), pyridine (1.78 mL) and 4-dimethylaminopyridine (0.12 g) were added.After stirring at room temperature for 2 hrs., ethyl acetate (50 mL) wasadded to the reaction mixture, and the mixture was washed with water (50mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50mL). After drying over anhydrous magnesium sulfate, the mixture wasconcentrated under reduced pressure. To the residue was added a 4Nhydrogen chloride-ethyl acetate solution (20 mL), and the mixture wasstirred at room temperature for 2 hrs. Diethyl ether (10 mL) was added,and the precipitated solid was collected by filtration. The solid wasdried under reduced pressure to give the title compound (2.93 g) as awhite solid.

¹H-NMR(DMSO-d₆): 2.07 (3H, s), 2.53 (3H, s), 3.12-3.17 (2H, m),4.24-4.30 (2H, m), 9.29 (2H, br).

Reference Example 3 2-(Methylamino)ethyl trimethylacetate hydrochloride

To a mixture of tert-butyl hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (15 mL) was addedtriethylamine (1.67 mL) and a mixture of trimethylacetyl chloride (1.35mL), and ethyl acetate (5 mL) was dropwise added. After stirring at roomtemperature for 2 hrs., pyridine (1.62 mL) was added, and the mixturewas stirred overnight at room temperature. Ethyl acetate (50 mL) wasadded to the reaction mixture, and the mixture was washed with water (50mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50mL), and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, a 4N hydrogen chloride-ethyl acetate solution(10 mL) was added to the residue. After stirring at room temperature for2 hrs., diethyl ether (10 mL) was added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (1.65 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.18 (9H, s), 2.56 (3H, s), 3.17 (2H, t, J=10.5 Hz),4.22-4.28 (2H, m), 9.19 (2H, br).

Reference Example 4 2-(Methylamino)ethyl cyclohexanecarboxylatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (20 mL) were addedpyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), andcyclohexanecarbonyl chloride (1.60 mL) was dropwise added.

After stirring at room temperature for 2 hrs., pyridine (0.65 mL) andcyclohexanecarbonyl chloride (0.58 mL) were added, and the mixture wasstirred overnight at room temperature. Ethyl acetate (50 mL) was addedto the reaction mixture, and the mixture was washed with water (50 mL),a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL),and dried over anhydrous magnesium sulfate. After concentration underreduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL)was added to the residue. After stirring at room temperature for 2 hrs.,diethyl ether (10 mL) was added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (1.88 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.10-1.45 (5H, m), 1.54-1.73 (3H, m), 1.83-1.93 (2H,m), 2.29-2.42 (1H, m), 2.54 (3H, s), 3.12-3.18 (2H, m), 4.23-4.29 (2H,m), 9.23 (2H, br).

Reference Example 5 2-(Methylamino)ethyl benzoate hydrochloride

To a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90mL) was dropwise added a mixture of di-tert-butyl Bicarbonate (87.30 g)and ethyl acetate (10 mL) under ice-cooling. After stirring at roomtemperature for 1 hr., benzoyl chloride (61.8 g) and pyridine (38.8 mL)were added under ice-cooling. After stirring at room temperature for 1hr., a solid was filtered off. The solid was washed with ethyl acetate(100 mL) and the filtrate and the washing were combined, which waswashed with water (100 mL) and saturated brine (100 mL). After dryingover anhydrous magnesium sulfate, the mixture was concentrated underreduced pressure. The residue was dissolved in ethyl acetate (100 mL), a4N hydrogen chloride-ethyl acetate solution (200 mL) was added, and themixture was stirred at room temperature for 30 min. Diethyl ether (100mL) was added and a solid was collected by filtration. The solid waswashed twice with ethyl acetate (100 mL) and dried under reducedpressure at 60° C. to give the title compound (57.4 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J=9.9 Hz),7.51-7.57 (2H, m), 7.68 (1H, m), 8.11 (2H, d, J=7.8 Hz), 9.26 (2H, bs).

Reference Example 6 2-(Methylamino)ethyl 4-methoxybenzoate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added4-methoxybenzoyl chloride (1.88 g) and pyridine (0.97 mL). Afterstirring at room temperature for 14 hrs., 4-methoxybenzoyl chloride(0.70 g) and pyridine (0.97 mL) were added and the mixture was stirredat room temperature for 1 hr. Ethyl acetate (80 mL) was added to thereaction mixture, and the mixture was washed with water (20 mL), asaturated aqueous sodium hydrogen carbonate solution (20 mL) and water(20 mL), and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was dissolved in ethyl acetate (10mL), and a 4N hydrogen chloride-ethyl acetate solution (10 mL) wasadded. After stirring at room temperature for 1 hr., diethyl ether (20mL) was added, and the precipitated solid was collected by filtration.The solid was washed twice with ethyl acetate (15 mL) and dried underreduced pressure at 60° C. to give the title compound (1.99 g) as awhite solid.

¹H-NMR(DMSO-d₆): 2.62 (3H, s), 3.32 (2H, m), 4.48 (2H, t, J=5.0 Hz),7.07 (2H, d, J=8.7 Hz), 8.06 (2H, d, J=8.7 Hz), 9.04 (2H, bs).

Reference Example 7 2-(Methylamino)ethyl 3-chlorobenzoate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added3-chlorobenzoyl chloride (1.92 g) and pyridine (0.97 mL). After stirringat room temperature for 1 hr., the mixture was stirred at 60° C. for 6hrs. Ethyl acetate (80 mL) was added to the reaction mixture, and themixture was washed with water (20 mL), a saturated aqueous sodiumhydrogen carbonate solution (20 mL) and water (20 mL), and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to theresidue. After stirring at room temperature for 22 hrs., diethyl ether(15 mL) was added, and the precipitated solid was collected byfiltration.

The solid was washed twice with ethyl acetate (15 mL) and dried underreduced pressure at 60° C. to give the title compound (2.01 g) as awhite solid.

¹H-NMR(DMSO-d₆): 2.63 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J=4.9 Hz),7.60 (1H, t, J=8.0 Hz), 7.78 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz),8.15 (1H, s), 9.07 (2H, bs).

Reference Example 8 2-(Methylamino)ethyl 3,4-difluorobenzoatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added3,4-difluorobenzoyl chloride (1.77 g) and pyridine (0.97 mL). Afterstirring at room temperature for 3 days, ethyl acetate (80 mL) was addedto the reaction mixture. The mixture was washed with water (20 mL), asaturated aqueous sodium hydrogen carbonate solution (20 mL) and water(20 mL), and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, a 4N hydrogen chloride-ethyl acetate solution(10 mL) was added to the residue. After stirring at room temperature for4 hrs, the mixture was concentrated under reduced pressure. The residuewas washed with ethyl acetate (15 mL), and dried under reduced pressureat 60° C. to give the title compound (2.05 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J=5.0 Hz),7.64 (1H, m), 8.00 (1H, m), 8.25 (1H, m), 9.25 (2H, bs).

Reference Example 9 2-(Methylamino)ethyl 4-trifluoromethoxybenzoatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.30 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added4-trifluoromethoxybenzoyl chloride (1.83 g) and pyridine (0.72 mL). Themixture was stirred at 60° C. for 25 hrs. Ethyl acetate (60 mL) wasadded to the reaction mixture, and the mixture was washed with water (30mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) andwater (20 mL), and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, a 4N hydrogen chloride-ethylacetate solution (10 mL) was added to the residue. After stirring atroom temperature for 14.5 hrs., the mixture was concentrated underreduced pressure. The residue was washed twice with ethyl acetate (15mL), and dried under reduced pressure at 60° C. to give the titlecompound (1.83 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.63 (3H, s), 3.31 (2H, m), 4.54 (2H, t, J=4.9 Hz),7.55 (2H, d, J=8.5 Hz), 8.24 (2H, d, J=8.5 Hz), 9.02 (2H, bs).

Reference Example 10 2-(Methylamino)ethyl 4-fluorobenzoate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added4-fluorobenzoyl chloride (1.74 g) and pyridine (0.97 mL). The mixturewas stirred at room temperature for 6.5 hrs. Ethyl acetate (80 mL) wasadded to the reaction mixture, and the mixture was washed with water (30mL), a saturated aqueous sodium hydrogen carbonate solution (30 mL),water (30 mL) and saturated brine (30 mL), and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, a 4Nhydrogen chloride-ethyl acetate solution (10 mL) was added to theresidue. After stirring at room temperature for 1 hr., the precipitatedsolid was collected by filtration. The solid was washed twice with ethylacetate (15 mL) and dried under reduced pressure at 60° C. to give thetitle compound (1.89 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.62 (3H, s), 3.32 (2H, m), 4.52 (2H, t, J=4.9 Hz),7.34-7.44 (2H, m), 8.16-8.24 (2H, m), 9.18 (2H, bs).

Reference Example 11 2-(Methylamino)ethyl 3,4,5-trimethoxybenzoatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were added3,4,5-trimethoxybenzoyl chloride (2.54 g) and pyridine (0.97 mL). Afterstirring at 60° C. for 14 hrs., 3,4,5-trimethoxybenzoyl chloride (1.30g), pyridine (0.97 mL) and ethyl acetate (10 mL) were added, and themixture was stirred at 60° C. for 24 hrs. The reaction mixture wasfiltered and ethyl acetate (50 mL) and water (30 mL) were added to thefiltrate. After partitioning, ethyl acetate layer was washed with 1Nhydrochloric acid (30 mL), water (30 mL), an aqueous copper (II) sulfatesolution (30 mL), water (30 mL) and saturated brine (30 mL), and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:1). A 4N hydrogen chloride-ethylacetate solution (10 mL) was added to the purified product. Afterstirring at room temperature for 4 hrs, the mixture was concentratedunder reduced pressure. Toluene (10 mL) was added, and the mixture wasconcentrated under reduced pressure. The residue was suspended in ethylacetate, and the solid was filtrated. After washing with ethyl acetate(15 mL), the solid was dried under reduced pressure to give the titlecompound (1.79 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.61 (3H, s), 3.28-3.35 (2H, m), 3.74 (3H, s), 3.87(6H, s), 4.48-4.54 (2H, m), 7.40 (2H, s), 9.43 (2H, br).

Reference Example 12 2-(Methylamino)ethyl 2-pyridinecarboxylatedihydrochloride

To a solution (100 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate(1.75 g) obtained in Reference Example 1, 2-pyridinecarbonyl chloridehydrochloride (2.67 g), pyridine (1.21 mL) and 4-dimethylaminopyridine(0.122 g) in tetrahydrofuran was dropwise added triethylamine (2.09 mL)under ice-cooling, and the mixture was stirred at room temperature for 6hrs. Water (200 mL) was added to the reaction mixture and the mixturewas extracted with ethyl acetate (150 mL). The organic layer was washedsuccessively with a 5% aqueous copper (II) sulfate solution (100 mL),water (100 mL) and saturated brine (100 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was dissolvedin ethyl acetate (50 mL) and ethanol (100 mL), and a 4N hydrogenchloride-ethyl acetate solution (15 mL) was added. The mixture wasstirred at room temperature for 1 hr. The precipitated solid wascollected by filtration, washed twice with ethyl acetate (100 mL), anddried under reduced pressure at 60° C. to give the title compound (1.08g) as a white solid.

¹H-NMR(DMSO-d₆): 2.62 (3H, t, J=5.4 Hz), 3.35 (2H, m), 4.63 (2H, t,J=5.0 Hz), 5.26 (1H, bs), 7.77-7.84 (1H, m), 8.14-8.18 (1H, m),8.36-8.40 (1H, m), 8.70-8.90 (1H, m), 9.48 (2H, br).

Reference Example 13 2-(Methylamino)ethyl methoxyacetate

To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (10 mL) were addedmethoxyacetyl chloride (1.20 g) and pyridine (0.97 mL). After stirringat room temperature for 3 hrs., ethyl acetate (70 mL) was added to thereaction mixture. The mixture was washed with water (20 mL), a saturatedaqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL),and dried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in ethyl acetate (5 mL), anda 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. Afterstirring at room temperature for 1 hr., the mixture was concentratedunder reduced pressure. Water (60 mL) and diethyl ether (30 mL) wereadded to the residue. After stirring, the aqueous layer was separatedand taken. The aqueous layer was basified with sodium hydrogen carbonateand extracted twice with ethyl acetate (40 mL). The ethyl acetate layerwas dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound (1.00 g) as a colorless oil.

¹H-NMR(CDCl₃): 2.40 (1H, bs), 3.06 (3H, s), 3.44 (3H, s), 3.57 (2H, t,J=5.1 Hz), 3.75-3.82 (2H, m), 4.13 (2H, s).

Reference Example 14 Ethyl 2-(methylamino)ethyl carbonate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (20 mL) were addedpyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), andethyl chlorocarbonate (1.25 mL) was dropwise added. The mixture wasstirred overnight at room temperature and ethyl acetate (50 mL) wasadded. The mixture was washed with water (50 mL), a 5% aqueous citricacid solution (50 mL) and saturated brine (50 mL), and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to theresidue. After stirring at room temperature for 2 hrs., diethyl ether(10 mL) was added, and the precipitated solid was collected byfiltration. The solid was dried under reduced pressure to give the titlecompound (1.66 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.23 (3H, t, J=7.1 Hz), 2.54 (3H, s), 3.16-3.22 (2H,m), 4.15 (2H, q, J=7.1 Hz), 4.32-4.37 (2H, m), 9.25 (2H, br).

Reference Example 15 Isopropyl 2-(methylamino)ethyl carbonatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g)obtained in Reference Example 1 and ethyl acetate (20 mL) were addedisopropyl chlorocarbonate (1.35 g) and pyridine (1.94 mL) underice-cooling. After stirring under ice-cooling for 3.5 hrs., isopropylchlorocarbonate (1.84 g) was added, and the mixture was stirred at roomtemperature for 2.5 hrs. Ethyl acetate (120 mL) was added to thereaction mixture, and the mixture was washed with water (50 mL) andsaturated brine (50 mL), and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, a 4N hydrogen chloride-ethylacetate solution (10 mL) was added to the residue. After stirring atroom temperature for 2 hrs., the precipitated solid was collected byfiltration. The solid was washed with ethyl acetate (15 mL), and driedunder reduced pressure at 60° C. to give the title compound (1.38 g) asa white solid.

¹H-NMR(DMSO-d₆): 1.25 (6H, d, J=6.2 Hz), 2.56 (3H, s), 3.20 (2H, t,J=5.1 Hz), 4.32 (2H, t, J=5.1 Hz), 4.80 (1H, m), 8.95 (2H, bs).

Reference Example 16 Benzyl 2-(methylamino)ethyl carbonate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (20 mL) were addedpyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), andbenzyl chlorocarbonate (1.57 mL) was dropwise added. After stirring atroom temperature for 2 hrs., pyridine (0.65 mL) and benzylchlorocarbonate (1.28 mL) were added. After stirring at room temperaturefor 5 days, pyridine (0.81 mL) was added under ice-cooling and asolution (5 mL) of benzyl chlorocarbonate (1.43 mL) in ethyl acetate wasdropwise added slowly. After stirring at room temperature for 2 hrs.,ethyl acetate (50 mL) was added to the mixture, washed with water (50mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50mL), and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, a 4N hydrogen chloride-ethyl acetate solution(10 mL) was added to the residue. After stirring at room temperature for2 hrs., diethyl ether (10 mL) was added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (1.99 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.55 (3H, s), 3.21 (2H, t, J=5.1 Hz), 4.37 (2H, t,J=5.1 Hz), 5.18 (2H, s), 7.30-7.50 (5H, m), 9.07 (2H, br).

Reference Example 17 2-(Methylamino)ethyl tetrahydropyran-4-yl carbonatehydrochloride

To a solution (40 mL) of bis(trichloromethyl)carbonate (2.97 g) intetrahydrofuran was dropwise added a solution (10 mL) of pyridine (2.43mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., a solution (20 mL) of tetrahydropyran-4-ol(1.91 g) in tetrahydrofuran was dropwise added slowly. After stirring atroom temperature for 2 hrs., the mixture was concentrated under reducedpressure, and ethyl acetate (50 mL) and water (50 mL) were added to theresidue. The ethyl acetate layer was separated and taken, washed with0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and driedover anhydrous magnesium sulfate. Concentration under reduced pressuregave tetrahydropyran-4-yl chlorocarbonate (1.53 g). To a mixture oftert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained inReference Example 1 and tetrahydrofuran (20 mL) was added pyridine (0.78mL), and a solution (10 mL) of tetrahydropyran-4-yl chlorocarbonate(1.53 g) obtained above in tetrahydrofuran was dropwise added, and themixture was stirred overnight at room temperature. After concentrationof the reaction mixture under reduced pressure, water (50 mL) was added,the mixture was extracted with ethyl acetate (50 mL). The residue waswashed with a 5% aqueous citric acid solution (50 mL) and saturatedbrine (50 mL), and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography (eluted with ethyl acetate:hexane=4:1, then3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether(2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) wasadded. After stirring at room temperature for 30 min., diethyl ether (10mL) was added and the mixture was stirred overnight. The precipitatedsolid was collected by filtration and dried under reduced pressure togive the title compound (1.20 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.50-1.65 (2H, m), 1.87-1.98 (2H, m), 2.54 (3H, s),3.20 (2H, m), 3.40-3.50 (2H, m), 3.74-3.83 (2H, m), 4.36 (2H, t, J=5.1Hz), 4.72-4.83 (1H, m), 9.32 (2H, br).

Reference Example 18 2-Methoxyethyl 2-(methylamino)ethyl carbonatehydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g)obtained in Reference Example 1 and ethyl acetate (20 mL) was addedpyridine (1.62 mL) and a solution (5 mL) of 2-methoxyethylchlorocarbonate (2.77 g) in ethyl acetate was dropwise added slowly, andthe mixture was stirred overnight at room temperature. Afterconcentration of the reaction mixture under reduced pressure, water (50mL) was added, the mixture was extracted with ethyl acetate (50 mL). Themixture was washed with 5% aqueous citric acid solution (50 mL) andsaturated brine (50 mL), and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was dissolved indiethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution(5 mL) was added. After stirring at room temperature for 30 min.,diethyl ether (10 mL) was added, and the mixture was stirred overnight.The precipitated solid was collected by filtration, and dried underreduced pressure to give the title compound (1.56 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.54 (3H, s), 3.19 (2H, m), 3.26 (3H, s), 3.52-3.57(2H, m), 4.20-4.25 (2H, m), 4.33-4.39 (2H, m), 9.26 (2H, br).

Reference Example 19 tert-Butyl ethyl(2-hydroxyethyl)carbamate

To a mixture of 2-(ethylamino)ethanol (8.91 g) and ethyl acetate (100mL) was added di-tert-butyl dicarbonate (21.8 g) under ice-cooling.After stirring at room temperature for 3 days, the mixture was washedwith saturated brine (100 mL), and dried over anhydrous magnesiumsulfate. Concentration under reduced pressure gave the title compound(19.0 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.11 (3H, t, J=7.0 Hz), 1.47 (9H, s), 3.27 (2H, q, J=7.0Hz), 3.37 (2H, t, J=5.2 Hz), 3.73 (2H, q, J=5.2 Hz).

Reference Example 20 2-(Ethylamino)ethyl acetate hydrochloride

To a mixture of tert-butyl ethyl(2-hydroxyethyl)carbamate (1.89 g)obtained in Reference Example 19 and ethyl acetate (20 mL) were addedacetic anhydride (1.04 mL), pyridine (0.89 mL) and4-dimethylaminopyridine (0.061 g). After stirring at room temperaturefor 3 hrs., ethyl acetate (50 mL) was added, and the mixture was washedwith water (50 mL), a 5% aqueous citric acid solution (50 mL) andsaturated brine (50 mL). After drying over anhydrous magnesium sulfate,the mixture was concentrated under reduced pressure. A 4N hydrogenchloride-ethyl acetate solution (10 mL) was added to the residue, andthe mixture was stirred at room temperature for 1 hr. Ethyl acetate (10mL) and diethyl ether (20 mL) were added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (1.54 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.22 (3H, t, J=7.3 Hz), 2.07 (3H, s), 2.95 (2H, q,J=7.3 Hz), 3.15 (2H, t, J=5.3 Hz), 4.24-4.30 (2H, m), 9.17 (2H, br).

Reference Example 21 Tert-Butyl 2-hydroxyethyl(isopropyl)carbamate

To a solution (30 mL) of 2-(isopropylamino)ethanol (10.0 g) intetrahydrofuran was added di-tert-butyl dicarbonate (22.2 g), and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure and water (100 mL) was added tothe residue. The mixture was extracted with ethyl acetate (200 mL). Theethyl acetate layer was washed with saturated brine (100 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound (21.21 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.12 (6H, d, J=6.6 Hz), 3.30 (2H, t, J=5.0 Hz), 3.71 (2H,t, J=5.0 Hz), 3.80-4.30 (1H, m).

Reference Example 22 2-(Isopropylamino)ethyl acetate hydrochloride

To a solution (15 mL) of tert-butyl 2-hydroxyethyl(isopropyl)carbamate(5.0 g) obtained in Reference Example 21 in tetrahydrofuran were addedpyridine (6.0 mL) and acetic anhydride (2.79 mL) and the mixture wasstirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, water (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with a 5% aqueous citric acid solution(50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure. The obtained colorless oil wasdissolved in a 4N hydrogen chloride-ethyl acetate solution (10 mL), andthe mixture was stirred at room temperature for 1 hr. The precipitatedsolid was collected by filtration, and dried under reduced pressure togive the title compound (3.14 g) as a colorless solid.

¹H-NMR(DMSO-d₆): 1.25 (6H, d, J=6.6 Hz), 2.08 (3H, s), 3.10-3.40 (3H,m), 4.29 (2H, t, J=6.0 Hz), 9.11 (2H, br).

Reference Example 23 Ethyl 2-(isopropylamino)ethyl carbonatehydrochloride

To a solution (15 mL) of tert-butyl 2-hydroxyethyl(isopropyl)carbamate(5.0 g) obtained in Reference Example 21 in tetrahydrofuran were addedpyridine (6.0 mL) and ethyl chlorocarbonate (2.81 mL) and the mixturewas stirred at room temperature for 18 hrs. The reaction mixture wasconcentrated under reduced pressure, and water (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with a 5% aqueous citric acid solution(50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfateand the mixture was concentrated under reduced pressure. The obtainedcolorless oil was dissolved in a 4N hydrogen chloride-ethyl acetatesolution (10 mL), and the mixture was stirred at room temperature for 1hr. The precipitated solid was collected by filtration and dried underreduced pressure to give the title compound (3.34 g) as a colorlesssolid.

¹H-NMR(DMSO-d₆): 1.20-1.30 (9H, m), 3.10-3.40 (3H, m), 4.17 (2H, q,J=7.4 Hz), 4.37 (2H, t, J=5.6 Hz), 9.13 (2H, br).

Reference Example 24 tert-Butyl cyclohexyl(2-hydroxyethyl)carbamate

To a solution (200 mL) of 2-(cyclohexylamino)ethanol (14.3 g) in ethanolwas dropwise added di-tert-butyl dicarbonate (21.8 g). After stirring atroom temperature for 2 days, the mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (200 mL), washedwith water (100 mL) and saturated brine (100 mL), and dried overanhydrous sodium sulfate. Concentration under reduced pressure gave thetitle compound (24.2 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.26-1.39 (4H, m), 1.47 (9H, s), 1.61-1.81 (6H, m),3.30-3.40 (2H, m), 3.69 (2H, t, J=5.4 Hz), 3.66-3.90 (2H, br).

Reference Example 25 2-(Cyclohexylamino)ethyl acetate hydrochloride

To a solution (50 mL) of tert-butyl cyclohexyl(2-hydroxyethyl)carbamate(2.43 g) obtained in Reference Example 24 in tetrahydrofuran were addedpyridine (1.05 mL), acetic anhydride (1.23 mL) and4-dimethylaminopyridine (0.122 g) under ice-cooling, and the mixture wasstirred at room temperature for 12 hrs. Ethyl acetate (100 mL) was addedto the reaction mixture and the mixture was washed successively with asaturated aqueous sodium hydrogen carbonate solution (100 mL), a 5%aqueous copper (II) sulfate solution (100 mL) and saturated brine (100mL), and dried over anhydrous sodium sulfate. The mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (15 mL), and a 4N hydrogen chloride-ethyl acetate solution (15mL) was added. After stirring at room temperature for 3 hrs.,diisopropyl ether (20 mL) was added, and the precipitated solid wascollected by filtration to give the title compound (1.78 g) as a whitesolid.

¹H-NMR(DMSO-d₆): 1.05-2.03 (10H, m), 2.07 (3H, s), 2.90-3.10 (1H, m),3.17 (2H, t, J=5.2 Hz), 4.29 (2H, t, J=5.2 Hz), 9.19 (2H, br).

Reference Example 26 2-(Cyclohexylamino)ethyl ethyl carbonatehydrochloride

To a solution (50 mL) of tert-butyl cyclohexyl(2-hydroxyethyl)carbamate(2.43 g) obtained in Reference Example 24 in tetrahydrofuran were addedpyridine (1.45 mL), ethyl chlorocarbonate (1.71 mL) and4-dimethylaminopyridine (0.122 g) under ice-cooling, and the mixture wasstirred at room temperature for 15 hrs. Ethyl acetate (100 mL) was addedto the reaction mixture, and the mixture was washed successively with asaturated aqueous sodium hydrogen carbonate solution (100 mL), a 5%aqueous copper (II) sulfate solution (100 mL), water (100 mL) andsaturated brine (100 mL), and dried over an hydrous sodium sulfate. Themixture was concentrated under reduced pressure and the residue wasdissolved in ethyl acetate (15 mL). A 4N hydrogen chloride-ethyl acetatesolution (15 mL) was added. After stirring at room temperature for 3hrs., diisopropyl ether (20 mL) was added, and the precipitated solidwas collected by filtration to give the title compound (2.12 g) as awhite solid.

¹H-NMR(DMSO-d₆): 1.01-2.08 (10H, m), 1.23 (3H, t, J=7.0 Hz), 2.90-3.10(1H, m), 3.21 (2H, t, J=5.2 Hz), 4.16 (2H, q, J=7.0 Hz), 4.39 (2H, t,J=5.2 Hz), 9.27 (2H, br).

Reference Example 27 2-Anilinoethyl acetate hydrochloride

To a solution (700 mL) of 2-anilinoethanol (137 g) in tetrahydrofuranwere added pyridine (97.1 mL), acetic anhydride (113.2 mL) and4-dimethylaminopyridine (12.22 g) under ice-cooling, and the mixture wasstirred at room temperature for 20 hrs. Ethyl acetate (1 L) was added tothe reaction mixture and the mixture was washed successively with water(1 L), a saturated aqueous sodium hydrogen carbonate solution (1 L), a5% aqueous copper (II) sulfate solution (1 L) and saturated brine (1 L),dried over anhydrous sodium sulfate, and evaporated under reducedpressure. To a solution of the obtained residue in ethyl acetate (700mL) was added a 4N hydrogen chloride-ethyl acetate solution (250 mL)under ice-cooling, and the precipitated solid was collected byfiltration to give the title compound (156 g) as a white solid.

¹H-NMR(CD₃OD): 2.11 (3H, s), 3.71-3.76 (2H, m), 4.32-4.37 (2H, m),7.49-7.64 (5H, m).

Reference Example 28 tert-Butyl [2-(methylamino)-3-pyridyl]methylcarbonate

To a solution (50 mL) of [2-(methylamino)-3-pyridyl]methanol (2 g:synthesized according to the method described in WO 01/32652) intetrahydrofuran were added di-tert-butyl dicarbonate (3.48 g) and4-dimethylaminopyridine (0.18 g) and the mixture was refluxed for 1 hr.Water (30 mL) was added to the reaction mixture and extracted with ethylacetate (50 mL). The obtained organic layer was washed with saturatedbrine (50 mL), and dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by flashsilica gel column chromatography (eluted with ethyl acetate:hexane=1:5)to give the title compound (1.51 g) as a white solid.

¹H-NMR(CDCl₃): 1.49 (9H, s), 3.02 (3H, d, J=4.8 Hz), 4.99 (2H, s), 5.00(1H, bs), 6.55 (1H, dd, J=7.0, 5.0 Hz), 7.37 (1H, dd, J=7.0, 1.8 Hz),8.16 (1H, dd, J=5.0, 1.8 Hz).

Reference Example 29 2-(Methylamino)benzyl acetate

To a solution (50 mL) of [2-(methylamino)phenyl]methanol (1.37 g:synthesized according to the method described in WO 01/32652) intetrahydrofuran were added pyridine (1.05 mL), acetic anhydride (1.23mL) and 4-dimethylaminopyridine (0.18 g), and the mixture was stirred atroom temperature for 8 hrs. Water (100 mL) was added to the reactionmixture, and the mixture was extracted with ethyl acetate (100 mL). Theorganic layer was washed successively with a 5% aqueous copper (II)sulfate solution (50 mL), a saturated aqueous sodium hydrogen carbonatesolution (50 mL) and saturated brine (50 mL), and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by flash silica gel columnchromatography (eluted with ethyl acetate:hexane=1:5, then 1:3) to givethe title compound (0.38 g) as a white solid.

¹H-NMR(CDCl₃): 2.08 (3H, s), 2.87 (3H, s), 4.40 (1H, br), 5.08 (2H, s),6.64-6.74 (2H, m), 7.17-7.32 (2H, m).

Reference Example 30 2-[(2-Acetyloxyethyl)amino]ethyl acetatehydrochloride

To a mixture of 2,2′-iminodiethanol (2.10 g) and ethyl acetate (20 mL)was added di-tert-butyl dicarbonate (4.37 g) under ice-cooling. Afterstirring for 1.5 hrs. under ice-cooling, acetic anhydride (2.08 mL),pyridine (1.78 mL) and 4-dimethylaminopyridine (0.12 g) were added.After stirring at room temperature for 2 hrs., ethyl acetate (50 mL) wasadded to the reaction mixture and the mixture was washed with water (50mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50mL). After drying over anhydrous magnesium sulfate, the mixture wasconcentrated under reduced pressure. A 4N hydrogen chloride-ethylacetate solution (20 mL) was added to the residue, and the mixture wasstirred at room temperature for 2 hrs. Diethyl ether (10 mL) was added,and the precipitated solid was collected by filtration. The solid wasdried under reduced pressure to give the title compound (6.18 g) as awhite solid.

¹H-NMR(DMSO-d₆): 2.07 (6H, s), 3.23 (4H, t, J=5.3 Hz), 4.27-4.33 (4H,m), 9.40 (2H, br).

Reference Example 31 (S)-2-Pyrrolidinylmethyl acetate hydrochloride

To a mixture of (S)-2-pyrrolidinylmethanol (1.01 g) and ethyl acetate(10 mL) was added di-tert-butyl dicarbonate (2.18 g) under ice-cooling.After stirring for 1 hr. under ice-cooling, acetic anhydride (1.04 mL),pyridine (0.89 mL) and 4-dimethylaminopyridine (0.061 g) were added.After stirring at room temperature for 1 hr., ethyl acetate (50 mL) wasadded to the reaction mixture, and the mixture was washed with water (50mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50mL). After drying over anhydrous magnesium sulfate, the mixture wasconcentrated under reduced pressure. A 4N hydrogen chloride-ethylacetate solution (10 mL) was added to the residue, and the mixture wasstirred at room temperature for 1 hr. Diethyl ether (10 mL) was addedand the precipitated solid was collected by filtration. The solid wasdried under reduced pressure to give the title compound (1.68 g) as apale-brown solid.

¹H-NMR(DMSO-d₆): 1.56-2.10 (4H, m), 2.06 (3H, s), 3.05-3.24 (2H, m),3.63-3.68 (1H, m), 4.15 (1H, dd, J=11.8, 8.1 Hz), 4.26 (1H, dd, J=11.8,4.1 Hz), 9.21 (1H, br), 9.87 (1H, br).

Reference Example 32 3-(Methylamino)propyl benzoate hydrochloride

To a mixture of 3-amino-1-propanol (0.75 g) and ethyl acetate (2.25 mL)was added a solution (0.25 mL) of di-tert-butyl dicarbonate (2.18 g) inethyl acetate under ice-cooling. After stirring at room temperature for21.5 hrs., benzoyl chloride (1.30 mL), pyridine (0.98 mL) and4-dimethylaminopyridine (0.012 g) were added. After stirring at roomtemperature for 5 hrs., ethyl acetate (32.5 mL) was added to thereaction mixture, and the mixture was washed with water (12.5 mL) andsaturated brine (12.5 mL). After drying over anhydrous magnesiumsulfate, the mixture was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (20 mL), and methyliodide (5 mL) was added. 60% sodium hydride (0.4 g) was added underice-cooling. After stirring at room temperature for 3 hrs., the reactionmixture was poured into an ice-cooled aqueous ammonium chloride solution(60 mL). The mixture was extracted with diethyl ether (80 mL) and washedwith saturated brine (30 mL). After drying over anhydrous magnesiumsulfate, the mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate:hexane=2:1, then ethyl acetate, then acetone:ethyl acetate=1:9)to give 3-[(tert-butoxycarbonyl)(methyl)amino]propyl benzoate (2.52 g)as a colorless oil. A 4N hydrogen chloride-ethyl acetate solution (10mL) was added, and the mixture was stirred at room temperature for 1 hr.After concentration under reduced pressure, ethyl acetate (10 mL) wasadded to the residue and the precipitated solid was collected byfiltration. After washing with diethyl ether (10 mL), the solid wasdried under reduced pressure to give the title compound (1.73 g) as acolorless solid.

¹H-NMR(DMSO-d₆): 2.02-2.16 (2H, m), 2.56 (3H, s), 3.05 (2H, t, J=7.3Hz), 4.35 (2H, t, J=6.1 Hz), 7.51 (2H, m), 7.65-7.73 (1H, m), 8.01 (2H,d, J=7.2 Hz), 8.95 (2H, br).

Reference Example 33 2-[(Ethoxycarbonyl)(methyl)amino]ethyl ethylcarbonate

To a solution (1000 mL) of 2-(methylamino)ethanol (100 g) in ethylacetate was added pyridine (222 mL), ethyl chlorocarbonate (240 mL) wasdropwise added over 2 hr. under ice-cooling. After the completion of thedropwise addition, the reaction mixture was stirred at room temperaturefor 18 hrs. Water (300 mL) was added, and the ethyl acetate layer wasseparated and washed with 1N hydrochloric acid (200 mL) and saturatedbrine (200 mL). After drying over anhydrous sodium sulfate, the mixturewas concentrated under reduced pressure, and the residue was evaporatedunder reduced pressure to give the title compound (180 g) as a colorlessfraction having a boiling point of 95-100° C. (pressure: 0.1-0.2 mmHg).

¹H-NMR(CDCl₃): 1.20-1.40 (6H, m), 2.97 (3H, s), 3.50-3.60 (2H, m),4.05-4.35 (6H, m).

Reference Example 34 2-[(Chlorocarbonyl)(methyl)amino]ethyl ethylcarbonate

To a solution (1500 mL) of 2-[(ethoxycarbonyl)(methyl)amino]ethyl ethylcarbonate (150 g) obtained in Reference Example 33 in acetonitrile wasadded phosphorus oxychloride (200 mL), and the mixture was refluxed for4 days. The reaction mixture was concentrated under reduced pressure andthe residue was added to a mixture of water (500 mL)-ice (700 g)-ethylacetate (300 mL) by portions with stirring. After stirring for 1 min.,saturated brine (500 mL) was added, and the mixture was extracted withethyl acetate (500 mL). The ethyl acetate layer was washed successivelywith saturated brine (300 mL), a saturated aqueous sodium hydrogencarbonate solution (300 mL) and saturated brine (300 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was evaporated under reduced pressure to give the title compound(77 g) as a colorless fraction having a boiling point of 100-105° C.(pressure: 0.1-0.2 mmHg).

¹H-NMR(CDCl₃): 1.33 (3H, t, J=7.2 Hz), 3.12 (3H×0.4,s), 3.22 (3H×0.6,s),3.68 (2H×0.6,t, J=4.8 Hz), 3.78 (2H×0.4,t, J=4.8 Hz), 4.23 (2H, q, J=7.2Hz), 4.30-4.40 (2H, m).

Reference Example 35 tert-Butyl 4-hydroxybutylcarbamate

To a mixture of 4-aminobutanol (3.57 g) and ethyl acetate (9 mL) wasdropwise added a mixture of di-tert-butyl dicarbonate (8.73 g) and ethylacetate (1 mL) under ice-cooling. After stirring at room temperature for24 hrs., the mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (200 mL), and the mixture waswashed with water (50 mL), 1N hydrochloric acid (40 mL), water (30 mL)and saturated brine (30 mL) and dried over anhydrous magnesium sulfate.Concentration under reduced pressure gave the title compound (7.54 g) asa colorless oil.

¹H-NMR(CDCl₃): 1.44 (9H, s), 1.47-1.61 (4H, m), 3.07-3.22 (2H, m),3.61-3.76 (2H, m), 4.62 (1H, bs).

Reference Example 3.6 4-[(tert-Butoxycarbonyl)amino]butyl acetate

To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained inReference Example 35 and ethyl acetate (20 mL) were added pyridine (1.80mL) and acetic anhydride (2.27 g), and the mixture was stirred at roomtemperature for 19 hrs. Ethyl acetate (100 mL) was added to the reactionmixture, and the mixture was washed with water (50 mL), an aqueouscopper sulfate solution (30 mL), water (30 mL) and saturated brine (30mL) and dried over anhydrous magnesium sulfate. Concentration underreduced pressure gave the title compound (4.55 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.44 (9H, s), 1.51-1.69 (4H, m), 2.05 (3H, s), 3.15 (2H,m), 4.07 (2H, t, J=6.5 Hz), 4.55 (1H, bs).

Reference Example 37 4-(Methylamino)butyl.acetate hydrochloride

To a solution (20 mL) of 4-[(tert-butoxycarbonyl)amino]butyl acetate(4.50 g) obtained in Reference Example 36 and methyl iodide (4.85 mL) inN,N-dimethylformamide was added sodium hydride (60% in oil, 0.94 g)under ice-cooling. After stirring at room temperature for 4 hrs., thereaction mixture was poured into an ice-aqueous ammonium chloridesolution. The mixture was extracted with diethyl ether (120 mL), and thediethyl ether layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:9). To the purified product wasadded a 4N hydrogen chloride-ethyl acetate solution (20 mL), and themixture was stirred at room temperature for 2 hrs. Diethyl ether (40 mL)was added, and the precipitated solid was collected by filtration. Thesolid was dried under reduced pressure to give the title compound (2.28g) as a white solid.

¹H-NMR(DMSO-d₆): 1.58-1.70 (4H, m), 2.01 (3H, s), 2.50 (3H, s),2.82-2.90 (2H, m), 4.00 (2H, t, J=6.0 Hz), 8.90 (2H, br).

Reference Example 38 4-[(tert-Butoxycarbonyl)amino]butyl ethyl carbonate

To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained inReference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and themixture was stirred at room temperature for 24 hrs. Ethyl acetate (100mL) was added to the reaction mixture, and the mixture was washed withwater (50 mL), an aqueous copper sulfate solution (30 ml), water (30 mL)and saturated brine (30 mL) and dried over anhydrous magnesium sulfate.Concentration under reduced pressure gave the title compound (4.92 g) asa colorless oil.

¹H-NMR(CDCl₃): 1.31 (3H, t, J=7.1 Hz), 1.44 (9H, s), 1.46-1.80 (4H, m),3.15 (2H, m), 4.11-4.25 (4H, m), 4.54 (1H, bs).

Reference Example 39 Ethyl 4-(methylamino)butyl carbonate hydrochloride

To a solution (20 mL) of 4-[(tert-butoxycarbonyl)amino]butyl ethylcarbonate (4.90 g) obtained in Reference Example 38 and methyl iodide(4.67 mL) in N,N-dimethylformamide was added sodium hydride (60% in oil,0.90 g) under ice-cooling. After stirring at room temperature for 6hrs., the reaction mixture was poured into an ice-aqueous ammoniumchloride solution, and extracted with diethyl ether (120 mL). Thediethyl ether layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:9). To the purified product wasadded a 4N hydrogen chloride-ethyl acetate solution (20 mL), and themixture was stirred at room temperature for 2 hrs. Diethyl ether (40 mL)was added, and the precipitated solid was collected by filtration. Thesolid was dried under reduced pressure to give the title compound (2.86g) as a white solid.

¹H-NMR(DMSO-d₆): 1.21 (3H, t, J=7.1 Hz), 1.51-1.73 (4H, m), 2.50 (3H,s), 2.82-2.94 (2H, m), 4.05-4.15 (4H, m), 8.88 (2H, br).

Reference Example 40 tert-Butyl 3-hydroxypropylcarbamate

To a mixture of 3-aminopropanol (7.51 g) and ethyl acetate (30 mL) wasdropwise added a mixture of di-tert-butyl dicarbonate (21.8 g) and ethylacetate (3 mL) under ice-cooling. After stirring at room temperature for22 hrs., the mixture was concentrated under reduced pressure.

The residue was dissolved in ethyl acetate (200 mL), washed with water(80 mL), 1N hydrochloric acid (60 mL), water (50 mL) and saturated brine(50 mL), and dried over anhydrous sodium sulfate. Concentration underreduced pressure gave the title compound (16.01 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.45 (9H, s), 1.62-1.70 (2H, m), 3.24 (2H, q, J=6.6 Hz),3.66 (2H, q, J=5.1 Hz), 4.73 (1H, bs).

Reference Example 41 3-[(tert-Butoxycarbonyl)amino]propyl acetate

To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained inReference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06mL) and acetic anhydride (5.13 g), and the mixture was stirred at roomtemperature for 21 hrs. Ethyl acetate (200 mL) was added to the reactionmixture, and the mixture was washed with water (100 mL), an aqueouscopper sulfate solution (40 mL), water (60 mL) and saturated brine (60mL), and dried over anhydrous sodium sulfate. Concentration underreduced pressure gave the title compound (8.34 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.44 (9H, s), 1.77-1.86 (2H, m), 2.06 (3H, s), 3.20 (2H,q, J=6.3 Hz), 4.12 (2H, t, J=6.3 Hz), 4.67 (1H, bs).

Reference Example 42 3-(Methylamino)propyl acetate hydrochloride

To a solution (80 mL) of 3-[(tert-butoxycarbonyl)amino]propyl acetate(17.28 g) obtained in Reference Example 41 and methyl iodide (19.8 mL)in N,N-dimethylformamide was added sodium hydride (60% in oil, 3.82 g)under ice-cooling. After stirring at room temperature for 15 hrs., thereaction mixture was poured into an ice-aqueous ammonium chloridesolution and extracted with diethyl ether (300 mL). The diethyl etherlayer was washed with saturated brine (100 mL), and dried over anhydroussodium sulfate. After concentration under reduced pressure, the residuewas purified by silica gel column chromatography (eluted with ethylacetate:hexane=1:8). To the purified product was added a 4N hydrogenchloride-ethyl acetate solution (40 mL), and the mixture was stirred atroom temperature for 2 hrs. Diethyl ether (100 mL) was added, and theprecipitated solid was collected by filtration. The solid was driedunder reduced pressure to give the title compound (2.93 g) as a whitesolid.

¹H-NMR(DMSO-d₆): 1.85-1.97 (2H, m), 2.02 (3H, s), 2.50 (3H, s),2.87-2.96 (2H, m), 4.06 (2H, t, J=6.3 Hz), 8.87 (2H, br).

Reference Example 43

3-[(tert-Butoxycarbonyl)amino]propyl ethyl carbonate

To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained inReference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06mL) and ethyl chlorocarbonate (5.95 g) under ice-cooling, and themixture was stirred at room temperature for 24 hrs. Ethyl acetate (100mL) was added to the reaction mixture, and the mixture was washed withwater (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL)and saturated brine (30 mL), and dried over anhydrous sodium sulfate.Concentration under reduced pressure gave the title compound (9.31 g) asa colorless oil.

¹H-NMR(CDCl₃): 1.31 (3H, t, J=7.1 Hz), 1.44 (9H, s), 1.82-1.90 (2H, m),3.22 (2H, t, J=6.3 Hz), 4.15-4.23 (4H, m), 4.68 (1H, bs).

Reference Example 44 Ethyl 3-(methylamino)propyl carbonate hydrochloride

To a solution (40 mL) of 3-[(tert-butoxycarbonyl)amino]propyl ethylcarbonate (9.31 g) obtained in Reference Example 43 and methyl iodide(9.00 mL) in N,N-dimethylformamide was added sodium hydride (60% in oil,1.82 g) under ice-cooling. After stirring at room temperature for 12hrs., the reaction mixture was poured into an ice-aqueous ammoniumchloride solution and the mixture was extracted with diethyl ether (200mL). The diethyl ether layer was washed with saturated brine (100 mL),and dried over anhydrous sodium sulfate. After concentration underreduced pressure, the residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=1:8). To the purifiedproduct was added a 4N hydrogen chloride-ethyl acetate solution (40 mL),and the mixture was stirred at room temperature for 2 hrs. Diethyl ether(200 mL) was added, and the precipitated solid was collected byfiltration. The solid was dried under reduced pressure to give the titlecompound (4.98 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.21 (3H, t, J=7.1 Hz), 1.91-2.00 (2H, m), 2.50 (3H,s), 2.88-2.98 (2H, m), 4.08-4.16 (4H, m), 8.90 (2H, br).

Reference Example 45 tert-Butyl(2,3-dihydroxypropyl)methylcarbamate

To a mixture of 3-(methylamino)-1,2-propanediol (24.5 g) and ethylacetate (50 mL) was dropwise added a mixture of di-tert-butyldicarbonate (51.4 g) and ethyl acetate (10 mL) under ice-cooling. Afterstirring at room temperature for 15 hrs., the mixture was concentratedunder reduced pressure. The residue was dissolved in ethyl acetate (150mL), and the solution was washed with water (80 mL), 1N hydrochloricacid (60 mL), water (50 mL) and saturated brine (50 mL), and dried overanhydrous sodium sulfate. Concentration under reduced pressure gave thetitle compound (26.9 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.47 (9H, s), 2.92 (3H, s), 3.20-3.36 (2H, m), 3.41 (2H,bs), 3.50-3.62 (2H, m), 3.73-3.88 (1H, m).

Reference Example 46 3-(Methylamino)propane-1,2-diyl diacetatehydrochloride

To a mixture of tert-butyl (2,3-dihydroxypropyl)methylcarbamate (10.26g) obtained in Reference Example 45 and ethyl acetate (50 mL) were addedpyridine (10.11 mL) and acetic anhydride (12.76 g), and the mixture wasstirred at room temperature for 24 hrs. Ethyl acetate (300 mL) was addedto the reaction mixture, and the mixture was washed with water (150 mL),an aqueous copper sulfate solution (100 mL), water (100 mL) andsaturated brine (100 mL), and dried over anhydrous sodium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography (eluted with ethyl acetate:hexane=1:8). To thepurified product was added a 4N hydrogen chloride-ethyl acetate solution(40 mL), and the mixture was stirred at room temperature for 3 hrs.Diethyl ether (100 mL) was added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (2.76 g) as a white solid.

¹H-NMR(DMSO-d₆): 2.03 (3H, s), 2.07 (3H, s), 2.55 (3H, s), 3.18-3.22(2H, m), 4.09-4.28 (2H, m), 5.20-5.27 (1H, m), 9.01 (2H, br).

Reference Example 47 Diethyl 3-(methylamino)propane-1,2-diylbiscarbonate hydrochloride

To a mixture of tert-butyl (2,3-dihydroxypropyl)methylcarbamate (15.53g) obtained in Reference Example 45 and ethyl acetate (100 mL) wereadded pyridine (18.35 mL) and ethyl chlorocarbonate (24.62 g) underice-cooling, and the mixture was stirred at room temperature for 96 hrs.Ethyl acetate (300 mL) was added to the reaction mixture, and themixture was washed with water (150 mL), an aqueous copper sulfatesolution (100 mL), water (100 mL) and saturated brine (100 mL), anddried over anhydrous sodium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:6). To the purified product wasadded a 4N hydrogen chloride-ethyl acetate solution (80 mL), and themixture was stirred at room temperature for 3 hrs. Diethyl ether (200mL) was added, and the precipitated solid was collected by filtration.The solid was dried under reduced pressure to give the title compound(5.93 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.20-1.28 (6H, m), 2.57 (3H, s), 3.12-3.28 (2H, m),4.10-4.43 (6H, m), 5.13-5.22 (1H, m), 9.14 (2H, br).

Reference Example 48 2-Ethoxyethyl 2-(methylamino)ethyl carbonatehydrochloride

To a solution (20 mL) of bis(trichloromethyl)carbonate (2.97 g) intetrahydrofuran was dropwise added a solution (10 mL) of 2-ethoxyethanol(1.80 g) in tetrahydrofuran under ice-cooling. Then a solution (10 mL)of pyridine (2.43 mL) in tetrahydrofuran was added dropwise, and themixture was stirred at room temperature for 2 hrs. The reaction mixturewas concentrated under reduced pressure and water (50 mL) was added tothe residue. The mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) andsaturated brine (50 mL), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give 2-ethoxyethylchlorocarbonate (1.29 g). A solution (15 mL) of tert-butyl2-hydroxyethyl(methyl)carbamate (1.23 g) obtained in Reference Example 1in tetrahydrofuran was added pyridine (0.68 mL), and a solution (5 mL)of 2-ethoxyethyl chlorocarbonate obtained above in tetrahydrofuran wasdropwise added to the mixture, and the mixture was stirred at roomtemperature for 3 days. After concentration of the reaction mixtureunder reduced pressure, water (50 mL) was added thereto and the mixturewas extracted with ethyl acetate (50 mL). The ethyl acetate layer waswashed with a 5% aqueous citric acid solution (50 mL) and saturatedbrine (50 mL), dried over anhydrous magnesium sulfate. The mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with ethyl acetate:hexane=1:5,then 2:3). The purified product (1.60 g) was dissolved in diethyl ether(3 mL) and a 4N hydrogen chloride-ethyl acetate solution (3 mL) wasadded. The mixture was stirred overnight at room temperature, and theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound (0.94 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.10 (3H, t, J=7.0 Hz), 2.57 (3H, s), 3.25 (2H, m),3.44 (2H, q, J=7.0 Hz), 3.56-3.60 (2H, m), 4.19-4.24 (2H, m), 4.30-4.37(2H, m), 8.79 (2H, br).

Reference Example 49 3-Methoxypropyl 2-(methylamino)ethyl carbonatehydrochloride

To a mixture of lithium aluminum hydride (2.85 g) and diethyl ether (100mL) was dropwise added slowly a solution (50 mL) of methyl3-methoxypropanoate (11.8 g) in tetrahydrofuran under ice-cooling. Afterstirring at room temperature for 1 hr., the mixture was again ice-cooledand water (3 mL) and a 10% aqueous sodium hydroxide solution (3 mL) weredropwise added. The mixture was allowed to reach room temperature, andwater (9 mL) was dropwise added. The mixture was stirred for a while.The precipitate was filtered off and the filtrate was concentrated underreduced pressure to give 3-methoxypropanol (7.64 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.83 (2H,quintet, J=5.8 Hz), 2.43 (1H, t, J=5.3 Hz), 3.36(3H, s), 3.57 (2H, t, J=6.0 Hz), 3.77 (2H, q, J=5.5 Hz).

To a solution (50 mL) of bis(trichloromethyl)carbonate (4.45 g) intetrahydrofuran was dropwise added N-ethyldiisopropylamine (5.75 mL)under ice-cooling. After stirring for a while, a solution (15 mL) of3-methoxypropanol (2.70 g) obtained above in tetrahydrofuran wasdropwise added. The mixture was stirred for 30 min. under ice-coolingand at room temperature for 1 day. After concentration of the reactionmixture under reduced pressure, diluted hydrochloric acid (50 mL) wasadded to the residue, and the mixture was extracted with ethyl acetate(80 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid(30 mL) and saturated brine (30 mL), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give 3-methoxypropylchlorocarbonate (4.39 g). To a solution (20 mL) of tert-butyl2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1in tetrahydrofuran was added pyridine (0.97 mL) and a solution (5 mL) ofa 3-methoxypropyl chlorocarbonate (1.83 g) obtained above intetrahydrofuran was dropwise added, and the mixture was stirred at roomtemperature for 2 hrs. A solution (5 mL) of pyridine (0.65 mL) and3-methoxypropyl chlorocarbonate (1.22 g) in tetrahydrofuran was addedand the mixture was further stirred for 1 hr. The reaction mixture wasconcentrated under reduced pressure and water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (80 mL), and theethyl acetate layer was washed with a 5% aqueous citric acid solution(50 mL) and saturated brine (50 mL), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted with ethylacetate:hexane=1:9, then 3:7). The purified product (3.40 g) wasdissolved in diethyl ether (5 mL) and a 4N hydrogen chloride-ethylacetate solution (5 mL) was added. The mixture was stirred overnight atroom temperature and the reaction mixture was concentrated under reducedpressure. Diethyl ether was added for crystallization to give the titlecompound (2.06 g) as a colorless solid.

¹H-NMR(DMSO-d₆): 1.78-1.90 (2H, m), 2.54 (3H, s), 3.15-3.25 (2H, m),3.23 (3H, s), 3.33-3.42 (2H, m), 4.16 (2H, t, J=6.0 Hz), 4.36 (2H, t,J=6.0 Hz), 9.27 (2H, br).

Reference Example 50 2-(Methylamino)ethyl N,N-dimethylglycinatedihydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g)obtained in Reference Example 1, N,N-dimethylglycine hydrochloride (5.29g), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (7.67g), triethylamine (5.58 mL), 4-dimethylaminopyridine (1.22 g) andN,N-dimethylformamide (50 mL) was stirred overnight at room temperature.The reaction mixture was concentrated under reduced pressure and asaturated aqueous sodium hydrogen carbonate solution (50 mL) was addedto the residue. The mixture was extracted with ethyl acetate (100 mL).The ethyl acetate layer was washed with saturated brine (50 mL), driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluted with methanol:ethyl acetate=5:95, then 20:80). 1N Hydrochloricacid (24 mL) was added to the purified product (2.46 g), and the mixturewas stirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure to give the title compound (2.14 g)as a colorless solid.

¹H-NMR(DMSO-d₆): 2.52 (3H, s), 2.85 (6H, s), 3.20 (2H, m), 4.30 (2H, s),4.43-4.49 (2H, m), 9.60 (2H, br), 10.81 (1H, br).

Reference Example 51 S-[2-(Methylamino)ethyl]thioacetate hydrochloride

To a solution (50 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate(3.50 g) obtained in Reference Example 1, thioacetic acid (1.72 mL) andtriphenylphosphine (7.87 g) in tetrahydrofuran was dropwise added slowlya solution (10 mL) of diisopropyl azodicarboxylate (5.91 mL) intetrahydrofuran under ice-cooling. The mixture was stirred underice-cooling for 1 hr. and at room temperature for 2 hrs. The reactionmixture was again ice-cooled and a solution (10 mL) oftriphenylphosphine (7.87 g) and diisopropyl azodicarboxylate (5.91 mL)in tetrahydrofuran was added. The mixture was stirred under ice-coolingfor 30 min. Thioacetic acid (1.14 mL) was added and the mixture wasstirred under ice-cooling for 30 min. and at room temperature overnight.The reaction mixture was concentrated under reduced pressure and hexaneand diisopropyl ether were added to the residue. The precipitate wasfiltered off and the filtrate was concentrated under reduced pressure.This step was repeated and a saturated aqueous sodium hydrogen carbonatesolution (50 mL) was added. The mixture was extracted with ethyl acetate(100 mL). The ethyl acetate layer was washed with saturated brine (50mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=5:95, and then 15:85).A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to thepurified product (4.47 g) and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure and ethyl acetate and diethyl ether were added to the residuefor crystallization to give the title compound (1.79 g) as a pale-yellowsolid.

¹H-NMR(DMSO-d₆): 2.38 (3H, s), 2.52 (3H, s), 2.96-3.08 (2H, m),3.12-3.20 (2H, m), 9.35 (2H, br).

Reference Example 52 Ethyl 2-[2-(methylamino)ethoxy]ethyl carbonatehydrochloride

To a mixture of 2-(2-aminoethoxy)ethanol (99.52 g) and ethyl acetate(200 mL) was dropwise added a mixture of di-tert-butyl dicarbonate(208.57 g) and ethyl acetate (50 mL) under ice-cooling. After stirringat room temperature for 60 hrs., the mixture was concentrated underreduced pressure. The residue was dissolved in ethyl acetate (500 mL),washed with water (200 mL), 1N hydrochloric acid (200 mL), water (300mL) and saturated brine (300 mL), and dried over anhydrous sodiumsulfate. Concentration under reduced pressure gave tert-butyl[2-(2-hydroxyethoxy)ethyl]carbamate (169.2 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.45 (9H, s), 3.33 (2H, q, J=5.1 Hz), 3.54-3.59 (4H, m),3.74 (2H, q, J=5.1 Hz), 4.88. (2H, bs).

To a mixture of tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (53.93 g)obtained above and ethyl acetate (350 mL) were added pyridine (53.78 mL)and ethyl chlorocarbonate (70.57 g) under ice-cooling, and the mixturewas stirred at room temperature for 96 hrs. Ethyl acetate (500 mL) wasadded to the reaction mixture, and the mixture was washed with water(500 mL), an aqueous copper sulfate solution (200 mL), water (300 mL)and saturated brine (300 mL) and dried over anhydrous sodium sulfate.Concentration under reduced pressure gave2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate (93.19 g)as a colorless oil.

¹H-NMR(CDCl₃): 1.32 (3H, t, J=7.2 Hz), 1.44 (9H, s), 3.32 (2H,t, J=5.1Hz), 3.54 (2H,t, J=5.1 Hz), 3.67-3.74 (2H, m), 4.21 (2H,q, J=7.2 Hz),4.26-4.31 (2H, m), 4.91 (1H, bs).

To a solution (350 mL) of 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethylethyl carbonate (93.15 g) obtained above and methyl iodide (83.6 mL) inN,N-dimethylformamide was added sodium hydride (60% in oil, 16.12 g)under ice-cooling. After stirring at room temperature for 24 hrs., thereaction mixture was poured into an ice-aqueous ammonium chloridesolution, and extracted with diethyl ether (800 mL). The diethyl etherlayer was washed with saturated brine (300 mL), and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withethyl acetate:hexane=1:8). To the purified product was added a 4Nhydrogen chloride-ethyl acetate solution (300 mL) was added, and themixture was stirred at room temperature for 2 hrs. Diethyl ether (300mL) was added, and the precipitated solid was collected by filtration.The solid was dried under reduced pressure to give the title compound(33.21 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.21 (3H, t, J=7.2 Hz), 2.51 (3H, s), 3.02-3.09 (2H,m), 3.65-3.72 (4H, m), 4.12 (2H, q, J=7.2 Hz), 4.22 (2H, t, J=4.5 Hz),9.06 (2H, br).

Reference Example 53 Ethyl2-[methyl[[2-(methylamino)ethoxy]carbonyl]amino]ethyl carbonatehydrochloride

To a solution (100 mL) of bis(trichloromethyl)carbonate (11.87 g) intetrahydrofuran was dropwise added a solution (20 mL) of pyridine (9.71mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., a solution (20 mL) of tert-butyl2-hydroxyethyl(methyl)carbamate (17.52 g) obtained in Reference Example1 in tetrahydrofuran was dropwise added and the mixture was stirred atroom temperature for 15 hrs. After concentration under reduced pressure,water (500 mL) and anhydrous sodium sulfate were added to the residue.After filtration, the filtrate was concentrated under reduced pressure.To the obtained residue were added a solution (50 mL) of2-(methylamino)ethanol (5.00 g) in ethyl acetate and triethylamine (10.0mL) under ice-cooling and the mixture was stirred at room temperaturefor 15 hrs. Ethyl acetate (300 mL) was added to the reaction mixture,washed with water (150 mL) and saturated brine (200 mL) and dried overanhydrous sodium sulfate. After concentration under reduced pressure, toa mixture of the residue and ethyl acetate (100 mL) were added pyridine(2.91 mL) and ethyl chlorocarbonate (3.44 g) under ice-cooling, and themixture was stirred at room temperature for 48 hrs. Ethyl acetate (200mL) was added to the reaction mixture, washed with water (100 mL), anaqueous copper sulfate solution (50 mL), water (50 mL) and saturatedbrine (50 mL), and dried over anhydrous sodium sulfate. The mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (eluted with ethyl acetate:hexane=1:3).To the purified product was added a 4N hydrogen chloride-ethyl acetatesolution (30 mL), and the mixture was stirred at room temperature for 3hrs. Diethyl ether (100 mL) was added, and the precipitated solid wascollected by filtration. The solid was dried under reduced pressure togive the title compound (2.90 g) as a white solid.

¹H-NMR(DMSO-d₆): 1.21 (3H, t, J=7.2 Hz), 2.57 (3H, bs), 2.86 (1.5H, s),2.93 (1.5H, s), 3.16 (2H, bs), 3.34 (1H, bs), 3.48 (1H, t, J=5.1 Hz),3.58 (1H, t, J=5.1 Hz), 4.12 (2H, q, J=7.2 Hz), 4.16-4.24 (4H, m), 8.94(1H, br).

Reference Example 54 2-(Methylamino)ethyl1-methylpiperidine-4-carboxylate dihydrochloride

A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide(2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) wasstirred at room temperature for 2 hrs. The reaction mixture wasconcentrated under reduced pressure and water (150 mL) was added. Themixture was extracted with ethyl acetate (150 mL). The ethyl acetatelayer was washed with saturated brine (100 mL), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. A 1N aqueoussodium hydroxide solution (20 mL) was added to the residue (2.64 g), andthe mixture was stirred overnight at room temperature. The reactionmixture was neutralized by adding 1N hydrochloric acid (20 mL) and themixture was concentrated under reduced pressure. Ethanol was added tothe residue, and the precipitate was filtered off. The filtrate wasconcentrated under reduced pressure. This step was repeated and ethanoland ethyl acetate were added to the residue for crystallization to give1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.

¹H-NMR(CD₃OD): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m),2.78 (3H, s), 2.88-3.04 (2H.m), 3.32-3.44 (2H.m).

A mixture of 1-methylpiperidine-4-carboxylic acid (1.72 g) obtainedabove, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained inReference Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimidehydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) andacetonitrile (50 mL) was stirred at room temperature for 16 hrs. Thereaction mixture was concentrated under reduced pressure and a saturatedaqueous sodium hydrogen carbonate solution (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with saturated brine (50 mL), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (elutedwith ethyl acetate:hexane=50:50, then 80:20). 1N Hydrochloric acid (25mL) was added to the purified product (2.73 g), and the mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure and isopropanol was added. Themixture was again concentrated under reduced pressure and theprecipitated solid was collected by filtration to give the titlecompound (1.72 g) as a colorless solid.

¹H-NMR(DMSO-d₆): 1.70-2.20 (4H, m), 2.40-3.50 (13H, m), 4.31 (2H, m),9.25 (2H, br), 10.77 (1H, br).

Reference Example 55 2-[[4-(Aminocarbonyl)phenyl]amino]ethyl acetate

A mixture of 4-fluorobenzonitrile (6.06 g), 2-aminoethanol (3.71 g),potassium carbonate (8.29 g) and dimethyl sulfoxide (50 mL) was stirredat 100° C. overnight. Water (200 mL) was added to the reaction mixtureand the mixture was extracted with ethyl acetate (200 mL×4). The ethylacetate layer was washed with saturated brine (100 mL), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluted withethyl acetate:hexane=30:70, then 50:50, then 80:20, then ethyl acetate)to give 4-[(2-hydroxyethyl)amino]benzonitrile (5.89 g) as a yellowsolid.

¹H-NMR(CDCl₃): 2.04 (1H, t, J=4.8 Hz), 3.33 (2H, m), 3.86 (2H, q, J=4.8Hz), 4.66 (1H, br), 6.58 (2H, d, J=8.7 Hz), 7.39 (2H, d, J=8.7 Hz).

A mixture of 4-[(2-hydroxyethyl)amino]benzonitrile (0.81 g) obtainedabove, potassium hydroxide (1.12 g) and tert-butanol (20 mL) was stirredat 100° C. for 1 hr. Water (100 mL) was added to the reaction mixture,and extracted with ethyl acetate (100 mL). The ethyl acetate layer waswashed with saturated brine (80 mL), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. To a solution (10 mL)of the residue (0.83 g), pyridine (0.49 mL) and 4-dimethylaminopyridine(0.061 g) in tetrahydrofuran was dropwise added a solution (1 mL) ofacetic anhydride (0.57 mL) in tetrahydrofuran. The mixture was stirredat room temperature for 1 hr., water (80 mL) was added, and the mixturewas extracted with ethyl acetate (100 mL). The ethyl acetate layer waswashed with saturated brine (80 mL), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluted with ethylacetate:hexane=30:70, then 60:40) to give the title compound (0.68 g) asa colorless solid.

¹H-NMR(CDCl₃): 2.08 (3H, s), 3.44 (2H, q, J=5.6 Hz), 4.29 (2H, t, J=5.4Hz), 4.48 (1H, br), 6.59 (2H, d, J=8.9 Hz), 7.43 (2H, d, J=8.9 Hz).

Reference Example 56 2-(Methylamino)ethyl 1-methyl-4-piperidinylcarbonate dihydrochloride

To a solution (40 mL) of N,N′-carbonyldiimidazole (3.36 g) intetrahydrofuran was dropwise added slowly a solution (10 mL) oftert-butyl 2-hydroxyethyl(methyl)carbamate (3.30 g) obtained inReference Example 1 in tetrahydrofuran under ice-cooling. The mixturewas stirred under ice-cooling for 40 min. and at room temperature for 2hrs. N,N′-Carbonyldiimidazole (0.31 g) was added and the mixture wasfurther stirred for 3 days. The reaction mixture was concentrated underreduced pressure and ethyl acetate (150 mL) was added to the residue.The mixture was washed with saturated brine (100 mL×2), water (50 mL×3)and saturated brine (50 mL), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give2-[(tert-butoxycarbonyl)(methyl)amino]ethyl 1H-imidazole-1-carboxylate(5.24 g) as a colorless oil.

¹H-NMR(CDCl₃): 1.39 (9H×0.5,s), 1.42 (9H×0.5,s), 2.94 (3H, m), 3.63 (2H,m), 4.51 (2H, t, J=5.3 Hz), 7.06 (1H, m), 7.42 (1H, m), 8.13 (1H, s).

A mixture of 2-[(tert-butoxycarbonyl)(methyl)amino]ethyl1H-imidazole-1-carboxylate (1.35 g) obtained above,1-methyl-4-piperidinol (1.38 g) and acetonitrile (20 mL) was stirredovernight at room temperature. 1-Methyl-4-piperidinol (0.92 g) was addedand the mixture was stirred overnight. The reaction mixture wasconcentrated under reduced pressure and a saturated aqueous sodiumhydrogen carbonate solution (50 mL) was added to the residue. Themixture was extracted with ethyl acetate (100 mL). The ethyl acetatelayer was washed with saturated brine (50 mL), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. 1NHydrochloric acid (12 mL) was added to the residue (1.60 g), and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, water, isopropanol and ethylacetate were added, and the precipitated solid was collected byfiltration to give the title compound (1.09 g) as a colorless solid.

¹H-NMR(DMSO-d₆): 1.85-2.20 (4H, m), 2.55 (3H, s), 2.70 (3H×0.5,s), 2.73(3H×0.5,s), 2.90-3.50 (6H, m), 4.38 (2H, m), 4.65-5.00 (1H, m), 9.21(2H, br), 11.10 (1H, br).

Synthetic Example 12-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl acetate hydrochloride(0.77 g) obtained in Reference Example 2 was added. A solution (1 mL) oftriethylamine (0.70 mL) in tetrahydrofuran was dropwise added and themixture was stirred at room temperature for 1 hr. After concentrationunder reduced pressure, water (50 mL) was added to the residue. Themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (50 mL) and dried over anhydrousmagnesium sulfate. The mixture was concentrated under reduced pressure,and the residue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue. The mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (50 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then ethylacetate), and further by silica gel column chromatography (eluted withethyl acetate:hexane=2:1, then ethyl acetate, then acetone:ethylacetate=1:4, then 1:1) to give the title compound (1.13 g) as a yellowamorphous solid.

¹H-NMR(CDCl₃): 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H,br), 4.25-4.50 (4H, m), 4.89 (1H, d, J=13.3 Hz), 5.05 (1H, d, J=13.3Hz), 6.65 (1H, d, J=5.5 Hz), 7.35-7.51 (3H, m), 7.80-7.90 (1H, m), 8.35(1H, d, J=5.5 Hz).

Synthetic Example 22-[Methyl[[(R)-2-[[[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyltrimethylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., 2-(methylamino)ethyl trimethylacetatehydrochloride (0.98 g) obtained in Reference Example 3 was added. Asolution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred overnight at roomtemperature. After concentration under reduced pressure, water (50 mL)was added to the residue. The mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with saturated brine (50mL), and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred overnight at 60° C. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (50 mL) and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by flash silica gel column chromatography(eluted with acetone:hexane=1:3, then 3:2). Crystallization fromacetone-diisopropyl ether and recrystallization from acetone-diisopropylether gave the title compound (1.01 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.23 (9H, s), 2.23 (3H, s), 3.08 (3H, bs), 3.40-4.30 (2H,br), 4.30-4.50 (4H, m), 4.80-5.20 (2H, br), 6.64 (1H, d, J=5.7 Hz),7.35-7.50 (3H, m), 7.78-7.88 (1H, m), 8.35 (1H, d, J=5.7 Hz).

Synthetic Example 32-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcyclohexanecarboxylate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl cyclohexane carboxylatehydrochloride (1.11 g) obtained in Reference Example 4 was added. Asolution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 1hr. After concentration under reduced pressure, water (50 mL) was addedto the residue. The mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred overnight at 60° C. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (50 mL) and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by flash silica gel column chromatography(eluted with acetone:hexane=1:3, then 3:2). Crystallization fromacetone-diisopropyl ether and recrystallization from acetone-diisopropylether gave the title compound (1.11 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.10-1.55 (5H, m), 1.55-1.82 (3H, m), 1.84-1.98 (2H, m),2.23 (3H, s), 2.27-2.40 (1H, m), 3.08 (3H, bs), 3.40-4.30 (2H, br),4.30-4.50 (4H, m), 4.80-5.15 (2H, br), 6.64 (1H, d, J=5.4 Hz), 7.35-7.48(3H, m), 7.84 (1H, d, J=6.9 Hz), 8.34 (1H, d, J=5.4 Hz).

Synthetic Example 42-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylbenzoate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., 2-(methylamino)ethyl benzoate hydrochloride (1.08g) obtained in Reference Example 5 was added. A solution (1 mL) oftriethylamine (0.70 mL) in tetrahydrofuran was dropwise added, and themixture was stirred overnight at room temperature. After concentrationunder reduced pressure, water (50 mL) was added to the residue. Themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (50 mL) and dried over anhydrousmagnesium sulfate. The layer was concentrated under reduced pressure,and the residue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred overnight at 60° C. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (50 mL) and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by flash silica gel column chromatography(eluted with acetone:hexane=1:3, then 3:2). Crystallization fromacetone-diethyl ether and recrystallization from acetone-diethyl ethergave the title compound (1.09 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 4.37(2H, q, J=7.8 Hz), 4.68 (2H, m), 4.80-5.20 (2H, br), 6.63 (1H, d, J=5.7Hz), 7.26-7.48 (5H, m), 7.53-7.61 (1H, m), 7.82 (1H, d, J=8.1 Hz), 8.04(2H, d, J=7.2 Hz), 8.33 (1H, d, J=5.7 Hz).

Synthetic Example 52-[Methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylbenzoate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.99 g) intetrahydrofuran was dropwise added a solution (2 mL) of pyridine (0.81mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl benzoate hydrochloride(2.16 g) obtained in Reference Example 5 was added. After addition of asolution (2 mL) of triethylamine (1.39 mL) in tetrahydrofuran, themixture was stirred at room temperature for 1 hr. After concentrationunder reduced pressure, ethyl acetate (100 mL) and water (100 mL) wereadded to the residue, and the mixture was stirred. The ethyl acetatelayer was separated and taken, washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (40 mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(2.90 g), triethylamine (2.20 mL) and 4-dimethylaminopyridine (0.096 g)were added, and the mixture was stirred at 60° C. for 2 hr. Afterconcentration under reduced pressure, ethyl acetate (150 mL) and water(80 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(50 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then ethylacetate). Recrystallization from acetone gave the title compound (2.62g) as a colorless solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.13 (3H, bs), 3.68-3.98 (2H,bm), 4.38 (2H,q, J=7.8 Hz), 4.69 (2H, m), 4.80-5.10 (2H,bm), 6.64 (1H, d, J=5.7 Hz),7.27-7.48 (5H, m), 7.59 (1H, m), 7.83 (1H, m), 8.06 (2H, d, J=6.0 Hz),8.35 (1H, d, J=5.7 Hz).

Synthetic Example 62-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl4-methoxybenzoate

To a solution (18 mL) of bis(trichloromethyl)carbonate (0.584 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 40 min., 2-(methylamino)ethyl 4-methoxybenzoatehydrochloride (1.48 g) obtained in Reference Example 6 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 80 min. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(50 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (30mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was dissolved in tetrahydrofuran (25mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.55 g), triethylamine (1.17 mL) and 4-dimethylaminopyridine (0.051 g)were added, and the mixture was stirred at 60° C. for 3 hrs. Afterconcentration under reduced pressure, ethyl acetate (150 mL) and water(50 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(50 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then ethylacetate). Recrystallization from ethyl acetate-hexane gave the titlecompound (1.08 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.11 (3H, bs), 3.68-3.90 (2H,bm), 3.85 (3H,s), 4.37 (2H, q, J=7.9 Hz), 4.58-4.72 (2H, m), 4.82-5.14 (2H,bm), 6.63(1H, d, J=5.7 Hz), 6.91 (2H, d, J=9.0 Hz), 7.27-7.40 (3H, m), 7.82 (1H,m), 7.99 (2H, d, J=9.0 Hz), 8.33 (1H, d, J=5.7 Hz).

Synthetic Example 72-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl3-chlorobenzoate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl 3-chlorobenzoatehydrochloride (1.50 g) obtained in Reference Example 7 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(40 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (25mL) and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.44 g), triethylamine (1.09 mL) and 4-dimethylaminopyridine (0.048 g)were added, and the mixture was stirred at 60° C. for 3 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(40 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (30mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by basic silica gelcolumn chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1)to give the title compound (0.84 g) as colorless syrup.

¹H-NMR(CDCl₃): 2.21 (3H, s), 3.12 (3H, bs), 3.78-4.08 (2H,bm), 4.38 (2H,q, J=7.8 Hz), 4.64-5.08 (4H,bm), 6.64 (1H, d, J=5.2 Hz), 7.34-7.42 (4H,m), 7.56 (1H, m), 7.82 (1H, m), 7.94 (1H, d, J=7.6 Hz), 8.02 (1H, s),8.34 (1H, d, J=5.2 Hz).

Synthetic Example 82-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl3,4-difluorobenzoate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl 3,4-difluorobenzoatehydrochloride (1.51 g) obtained in Reference Example 8 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 3 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(50 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (30mL) and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (25 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.71 g), triethylamine (1.29 mL) and 4-dimethylaminopyridine (0.056 g)were added, and the mixture was stirred at 60° C. for 17 hrs. Afterconcentration under reduced pressure, ethyl acetate (100 mL) and water(50 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, and the aqueous layer wasextracted with ethyl acetate (20 mL). Ethyl acetate layers werecombined, washed with saturated brine (30 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withethyl acetate:hexane=1:1, then 2:1), and by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1). Crystallizationfrom acetone-diisopropyl ether and recrystallization from ethylacetate-hexane gave the title compound (1.37 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.21 (3H, s), 3.11 (3H, bs), 3.82-4.08 (2H,bm), 4.38 (2H,q, J=7.8 Hz), 4.60-5.14 (4H,bm), 6.63 (1H, d, J=5.7 Hz), 7.20 (1H, m),7.33-7.41 (3H, m), 7.78-7.92 (3H, m), 8.33 (1H, d, J=5.7 Hz).

Synthetic Example 92-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl4-trifluoromethoxybenzoate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl 4-trifluoromethoxybenzoatehydrochloride (1.79 g) obtained in Reference Example 9 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 1.5 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(50 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (30mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was dissolved in tetrahydrofuran (25mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.57 g), triethylamine (1.18 mL) and 4-dimethylaminopyridine (0.052 g)were added, and the mixture was stirred at 60° C. for 4.5 hrs. Afterconcentration under reduced pressure, ethyl acetate (100 mL) and water(50 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, and the aqueous layer wasextracted with ethyl acetate (30 mL). The ethyl acetate layers werecombined, washed with saturated brine (30 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was purified by silica gel column chromatography (eluted withethyl acetate:hexane=1:1), and further by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1) to give the titlecompound (1.44 g) as colorless syrup.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.11 (3H, bs), 3.85-4.05 (2H,bm), 4.38 (2H,q, J=7.8 Hz), 4.60-5.12 (4H,bm), 6.64 (1H, d, J=5.7 Hz), 7.24 (2H, d,J=8.7 Hz), 7.25-7.40 (3H, m), 7.82 (1H, d, J=7.2 Hz), 8.09 (2H, d, J=8.7Hz), 8.33 (1H, d, J=5.7 Hz).

Synthetic Example 102-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl4-fluorobenzoate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl 4-fluorobenzoatehydrochloride (1.40 g) obtained in Reference Example 10 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(40 mL) were added to the residue and the mixture was stirred. The ethylacetate layer was separated and taken, washed with saturated brine (30mL) and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.32 g), triethylamine (1.00 mL) and 4-dimethylaminopyridine (0.049 g)were added, and the mixture was stirred at 60° C. for 14.5 hrs. Afterconcentration under reduced pressure, ethyl acetate (150 mL) and water(50 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(30 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was crystallized from ethylacetate:hexane=1:1 and collected by filtration. Recrystallization fromacetone gave the title compound (1.39 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.12 (3H, bs), 3.78-4.20 (2H,bm), 4.38 (2H,q, J=7.8 Hz), 4.58-5.08 (4H,bm), 6.65 (1H, d, J=5.6 Hz), 7.11 (2H, t,J=8.4 Hz), 7.28-7.44 (3H, m), 7.81-7.86 (1H, m), 8.03-8.11 (2H, m), 8.35(1H, d, J=5.6 Hz).

Synthetic Example 112-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl3,4,5-trimethoxybenzoate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.60 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., 2-(methylamino)ethyl 3,4,5-teimethoxybenzoatehydrochloride (1.22 g) obtained in Reference Example 11 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 1 hr.After concentration under reduced pressure, water (50 mL) was added tothe residue. The mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with dilute hydrochloric acid (20 mL) andsaturated brine (50 mL) and dried over anhydrous magnesium sulfate. Thelayer was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 3 hrs. and at roomtemperature for 2 days. After concentration under reduced pressure,water (50 mL) was added to the residue. The mixture was extracted withethyl acetate (50 mL). The ethyl acetate layer was washed with saturatedbrine (50 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by flashsilica gel column chromatography (eluted with acetone:hexane=1:3, then3:2) to give the title compound (1.56 g) as a yellow amorphous solid.

¹H-NMR (CDCl₃): 2.21 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 3.83(6H, s), 3.90 (3H, s), 4.38 (2H, q, J=7.8 Hz), 4.67 (2H, m), 4.80-5.15(2H, br), 6.64 (1H, d, J=5.7 Hz), 7.25-7.40 (5H, m), 7.78-7.86 (1H, m),8.33 (1H, d, J=5.7 Hz).

Synthetic Example 122-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl2-pyridinecarboxylate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.422 g) intetrahydrofuran was dropwise added pyridine (0.345 mL) underice-cooling. After stirring under ice-cooling for 30 min.,2-(methylamino)ethyl 2-pyridinecarboxylate dihydrochloride (1.08 g)obtained in Reference Example 12 was added. After dropwise addition oftriethylamine (1.19 mL), the mixture was stirred at room temperature for2 hrs. The precipitated solid was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), and(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.31 g), triethylamine (0.99 mL) and 4-dimethylaminopyridine (0.043 g)were added. The mixture was stirred at 60° C. for 24 hrs. Ethyl acetate(100 mL) was added to the reaction mixture, and the mixture was washedwith water (100 mL) and saturated brine (100 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluted with ethylacetate:hexane=4:1). Crystallization from acetone-diethyl ether gave thetitle compound (0.9 g) as a white solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.16 (3H, s), 3.80-4.20 (2H, m), 4.38 (2H,q, J=7.8 Hz), 4.60-5.10 (4H, m), 6.64 (1H, d, J=5.8 Hz), 7.29-7.40 (2H,m), 7.47-7.52 (2H, m), 7.81-7.89 (2H, m), 8.14 (1H, d, J=7.8 Hz), 8.34(1H, d, J=5.8 Hz), 8.75-8.79 (1H, m).

Synthetic Example 132-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylmethoxyacetate

To a solution (15 mL) of bis(trichloromethyl)carbonate (0.652 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.55mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl methoxyacetate (0.99 g)obtained in Reference Example 13 was added. The mixture was stirred atroom temperature for 3 hrs. After concentration under reduced pressure,ethyl acetate (80 mL) and water (50 mL) were added to the residue andthe mixture was stirred. The ethyl acetate layer was separated andtaken, washed with saturated brine (30 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was dissolved in tetrahydrofuran (15 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.13 g), triethylamine (0.86 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 4 days. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(30 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, and the ethyl acetate layerwas washed with a saturated aqueous sodium hydrogen carbonate solution(30 mL) and water (30 mL), and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bysilica gel column chromatography (eluted with ethyl acetate, thenacetone:ethyl acetate=1:3), and further by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then 3:1) to givethe title compound (0.588 g) as colorless syrup.

¹H-NMR(CDCl₃): 2.32 (3H, s), 2.68 (3H, s), 3.48 (3H, s), 3.69-4.02 (4H,m), 4.38 (2H, q, J=7.8 Hz), 4.67 (2H, t, J=6.6 Hz), 4.99 (1H, d, J=13.9Hz), 5.12 (1H, d, J=13.9 Hz), 6.63 (1H, d, J=5.7 Hz), 7.29-7.46 (2H, m),7.62 (1H, m), 7.81 (1H, m), 8.25 (1H, d, J=5.7 Hz).

Synthetic Example 14 Ethyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (40 mL) of bis(trichloromethyl)carbonate (1.31 g) intetrahydrofuran was dropwise added a solution (2 mL) of pyridine (1.07mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., ethyl 2-(methylamino)ethyl carbonatehydrochloride (2.02 g) obtained in Reference Example 14 was added. Asolution (2 mL) of triethylamine (1.84 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 1 hr.After concentration under reduced pressure, water (100 mL) was added tothe residue, and the mixture was extracted with ethyl acetate (100 mL).The ethyl acetate layer was washed with 0.2N hydrochloric acid (50 mL)and saturated brine (100 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was dissolved intetrahydrofuran (50 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(3.69 g), triethylamine (2.09 mL) and 4-dimethylaminopyridine (0.12 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 8 hrs. After concentration under reduced pressure, water(100 mL) was added to the residue, and the mixture was extracted withethyl acetate (100 mL). The ethyl acetate layer was washed withsaturated brine (100 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=3:7, then ethyl acetate). Crystallization from diethylether and recrystallization from diethyl ether gave the title compound(3.84 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.32 (3H, t, J=7.2 Hz), 2.23 (3H, s), 3.10 (3H, bs),3.50-4.20 (2H, br), 4.22 (2H, q, J=7.2 Hz), 4.39 (2H, q, J=7.9 Hz), 4.45(2H, m), 4.80-5.15 (2H, br), 6.65 (1H, d, J=5.6 Hz), 7.36-7.50 (3H, m),7.84 (1H, d, J=7.8 Hz), 8.35 (1H, d, J=5.6 Hz).

Synthetic Example 15 Isopropyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., isopropyl 2-(methylamino)ethyl carbonatehydrochloride (0.99 g) obtained in Reference Example 15 was added. Asolution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 1 hr.Bis(trichloromethyl)carbonate (0.50 g), a solution (1 mL) of pyridine(0.40 mL) in tetrahydrofuran and a solution (1 mL) of triethylamine(0.70 mL) in tetrahydrofuran were successively added and the mixture wasstirred at room temperature for 1 hr. After concentration under reducedpressure, water (50 mL) was added to the residue. The mixture wasextracted with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (50 mL) and dried over anhydrous magnesium sulfate.The layer was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 12 hrs. and atroom temperature for 3 days. After concentration under reduced pressure,water (50 mL) was added to the residue. The mixture was extracted withethyl acetate (50 mL). The ethyl acetate layer was washed with saturatedbrine (50 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by flashsilica gel column chromatography (eluted with acetone:hexane=1:3, then3:2), and further by basic silica gel column chromatography (eluted withethyl acetate:hexane=3:7, then ethyl acetate). Crystallization fromdiethyl ether and recrystallization from acetone-diisopropyl ether gavethe title compound (0.58 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.31 (6H, d, J=6.3 Hz), 2.23 (3H, s), 3.08 (3H, bs),3.40-4.30 (2H, br), 4.37 (2H, q, J=7.9 Hz), 4.32-4.53 (2H, m), 4.80-5.20(3H, m), 6.63 (1H, d, J=5.7 Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J=7.2Hz), 8.34 (1H, d, J=5.7 Hz).

Synthetic Example 16 Isopropyl2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., isopropyl 2-(methylamino)ethyl carbonatehydrochloride (1.18 g) obtained in Reference Example 15 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was addedand the mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, ethyl acetate (80 mL) and water(30 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(30 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was dissolved in tetrahydrofuran (25mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.73 g), triethylamine (1.31 mL) and 4-dimethylaminopyridine (0.057 g)were added, and the mixture was stirred at 60° C. for 5 hrs. Afterconcentration under reduced pressure, ethyl acetate (100 mL) and water(50 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(50 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by basic silica gelcolumn chromatography (eluted with ethyl acetate:hexane=1:1), andfurther by silica gel column chromatography (eluted with ethylacetate:hexane=1:1, then 2:1). Crystallization from diisopropylether-hexane and recrystallization from diisopropyl ether gave the titlecompound (1.20 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.31 (6H, d, J=6.6 Hz), 2.23 (3H, s), 3.08 (3H, bs),3.50-3.90 (2H,bm), 4.38 (2H, q, J=7.8 Hz), 4.36-4.58 (2H,bm), 4.79-5.15(3H, m), 6.64 (1H, d, J=5.7 Hz), 7.35-7.48 (3H, m), 7.83 (1H, d, J=7.5Hz), 8.34 (1H, d, J=5.7 Hz).

Synthetic Example 17 Benzyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., benzyl 2-(methylamino)ethyl carbonatehydrochloride (1.08 g) obtained in Reference Example 16 was added. Asolution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred overnight at roomtemperature. After concentration under reduced pressure, water (50 mL)was added to the residue. The mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with saturated brine (50 mL)and dried over anhydrous magnesium sulfate. The layer was concentratedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred overnight at 60° C. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (50 mL) and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by flash silica gel column chromatography(eluted with acetone:hexane=1:3, then 3:2). Crystallization fromacetone-diethyl ether and recrystallization from acetone-diethyl ethergave the title compound (1.17 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.22 (3H, s), 3.05 (3H, bs), 3.50-4.20 (2H, br), 4.37(2H, q, J=7.8 Hz), 4.46 (2H, m), 4.80-5.10 (2H, br), 5.17 (2H, s), 6.62(1H, d, J=5.6 Hz), 7.26-7.48 (8H, m), 7.77-7.88 (1H, m), 8.33 (1H, d,J=5.6 Hz).

Synthetic Example 182-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyltetrahydropyran-4-yl carbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.48 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.39mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 20 min., 2-(methylamino)ethyl tetrahydropyran-4-ylcarbonate hydrochloride (0.96 g) obtained in Reference Example 17 wasadded. A solution (1 mL) of triethylamine (0.67 mL) in tetrahydrofuranwas dropwise added, and the mixture was stirred at room temperature for2 hrs. After concentration under reduced pressure, water (50 mL) wasadded to the residue. The mixture was extracted with ethyl acetate (50mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20mL) and saturated brine (50 mL) and dried over anhydrous magnesiumsulfate. The layer was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.26 g), triethylamine (0.71 mL) and 4-dimethylaminopyridine (0.042 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 8 hrs. After concentration under reduced pressure, water(50 mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(50 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by basic silica gelcolumn chromatography (eluted with ethyl acetate:hexane=3:7, then ethylacetate). Crystallization from diethyl ether and recrystallization fromacetone-diisopropyl ether gave the title compound (1.45 g) as acolorless solid.

¹H-NMR(CDCl₃): 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.09(3H, bs), 3.40-4.30 (2H, br), 3.45-3.57 (2H, m), 3.87-3.97 (2H, m), 4.38(2H, q, J=7.8 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.64 (1H, d, J=5.7Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J=6.9 Hz), 8.35 (1H, d, J=5.7 Hz).

Synthetic Example 19 2-Methoxyethyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., 2-methoxyethyl 2-(methylamino)ethyl carbonatehydrochloride (1.07 g) obtained in Reference Example 18 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 1 hr.After concentration under reduced pressure, water (50 mL) was added tothe residue. The mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) andsaturated brine (50 mL) and dried over anhydrous magnesium sulfate. Thelayer was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.85 g), triethylamine (1.05 mL) and 4-dimethylaminopyridine (0.061 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 8 hrs. After concentration under reduced pressure, water(50 mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(50 mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was purified by basic silica gelcolumn chromatography (eluted with ethyl acetate:hexane=3:7, then ethylacetate). Crystallization from ethyl acetate-diethyl ether andrecrystallization from ethyl acetate-diisopropyl ether gave the titlecompound (1.39 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.23 (3H, s), 3.09 (3H, bs), 3.37 (3H, s), 3.50-4.20 (2H,br), 3.59-3.65 (2H, m), 4.28-4.33 (2H, m), 4.38 (2H, q, J=7.8 Hz), 4.46(2H, m), 4.80-5.15 (2H, br), 6.64 (1H, d, J=5.7 Hz), 7.35-7.47 (3H, m),7.83 (1H, d, J=7.8 Hz), 8.34 (1H, d, J=5.7 Hz).

Synthetic Example 202-[Ethyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., 2-(ethylamino)ethyl acetate hydrochloride (0.67g) obtained in Reference Example 20 was added. A solution (1 mL) oftriethylamine (0.84 mL) in tetrahydrofuran was dropwise added and themixture was stirred at room temperature for 1 hr. After concentrationunder reduced pressure, water (50 mL) was added to the residue. Themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (50 mL) and dried over anhydrousmagnesium sulfate. The layer was concentrated under reduced pressure,and the residue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred overnight at 60° C. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (50 mL) and dried overanhydrous magnesium sulfate. After concentration under reduced pressure,the residue was purified by basic silica gel column chromatography(eluted with ethyl acetate:hexane=3:7, then ethyl acetate) to give thetitle compound (1.58 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.25 (3H, m), 2.08 (3H, s), 2.23 (3H, s), 3.30-4.10 (4H,br), 4.23-4.45 (2H, m), 4.38 (2H, q, J=7.8 Hz), 4.75-5.20 (2H, br), 6.64(1H, d, J=5.7 Hz), 7.35-7.46 (3H, m), 7.84 (1H, d, J=6.9 Hz), 8.36 (1H,d, J=5.7 Hz).

Synthetic Example 212-[Isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.543 g) intetrahydrofuran was dropwise added a solution (5 mL) of pyridine (0.445mL) in tetrahydrofuran under ice-cooling, and the mixture was stirred at0° C. for 30 min. 2-(Isopropylamino)ethyl acetate hydrochloride (1.0 g)obtained in Reference Example 22 was added. A solution (5 mL) oftriethylamine (0.805 mL) in tetrahydrofuran was dropwise added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas concentrated under reduced pressure, water (30 mL) was added to theresidue. The mixture was extracted with ethyl acetate (50 mL). The ethylacetate layer was washed with saturated brine (30 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained oil was dissolved in tetrahydrofuran (5 mL), and added to asolution (20 mL) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.73 g), triethylamine (1.53 mL) and 4-dimethylaminopyridine (0.134 g)in tetrahydrofuran. The mixture was stirred at 40° C. for 12 hrs. Thereaction mixture was concentrated under reduced pressure and water (30mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(30 mL), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=2:1, then ethylacetate) to give the title compound (1.50 g) as a pale-yellow amorphoussolid.

¹H-NMR(CDCl₃): 1.20-1.40 (6H, m), 2.05 (3H×0.4,s), 2.11 (3H×0.6,s), 2.18(3H×0.6,s), 2.27 (3H×0.4,s), 3.40-3.60 (1H, m), 3.70-4.60 (6H, m),4.70-5.25 (2H, m), 6.65 (1H, d, J=5.8 Hz), 7.30-7.50 (3H, m), 7.75-7.90(1H, m), 8.37 (1H, d, J=5.8 Hz).

Synthetic Example 22 Ethyl2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.467 g) intetrahydrofuran was dropwise added a solution (5 mL) of pyridine (0.381mL) in tetrahydrofuran under ice-cooling, and the mixture was stirred at0° C. for 30 min. Ethyl 2-(isopropylamino)ethyl carbonate hydrochloride(1.0 g) obtained in Reference Example 23 was added to the reactionmixture. A solution (5 mL) of triethylamine (0.69 mL) in tetrahydrofuranwas dropwise added, and the mixture was stirred at 0° C. for 15 min. andat room temperature for 30 min. The reaction mixture was concentratedunder reduced pressure and water (30 mL) was added to the residue. Themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (30 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedoil was dissolved in tetrahydrofuran (5 mL), and added to a solution (20mL) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.48 g), triethylamine (1.32 mL) and 4-dimethylaminopyridine (0.115 g)in tetrahydrofuran, and the mixture was stirred at 40° C. for 12 hrs.The reaction mixture was concentrated under reduced pressure and water(30 mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(30 mL), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=2:1, then ethylacetate) to give the title compound (1.20 g) as a pale-yellow amorphoussolid.

¹H-NMR(CDCl₃): 1.20-1.40 (9H, m), 2.17 (3H×0.6,s), 2.27 (3H×0.4,s),3.40-3.70 (1H, m), 3.75-4.65 (8H, m), 4.70-5.30 (2H, m), 6.64 (1H, d,J=5.8 Hz), 7.35-7.55 (3H, m), 7.75-7.90 (1H, m), 8.38 (1H, d, J=5.8 Hz).

Synthetic Example 232-[Cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.593 g) intetrahydrofuran was dropwise added pyridine (0.485 mL) underice-cooling. After stirring under ice-cooling for 30 min.,2-(cyclohexylamino)ethyl acetate hydrochloride (1.33 g) obtained inReference Example 25 was added. Triethylamine (0.84 mL) was dropwiseadded, and the mixture was stirred at room temperature for 2 hrs. Ethylacetate (50 mL) was added to the reaction mixture and the mixture waswashed with water (50 mL) and saturated brine (50 mL), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (20 mL), and(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.61 g), triethylamine (1.21 mL) and 4-dimethylaminopyridine (0.053 g)were added. The mixture was stirred at 60° C. for 24 hrs. Ethyl acetate(50 mL) was added to the reaction mixture, and the mixture was washedwith water (20 mL) and saturated brine (50 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash silica gel column chromatography (eluted with ethylacetate:hexane=1:4, then ethyl acetate) to give the title compound (2.12g) as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.00-2.42 (16H, m), 3.30-3.70 (2H, m), 3.80-4.00 (1H, m),4.27-4.42 (2H, m), 4.40 (2H, q, J=8.2 Hz), 4.78 (1H×0.5, d, J=13.2 Hz),4.97 (2H×0.5,s), 5.20 (1H×0.5, d, J=13.2 Hz), 6.67 (1H, d, J=5.8 Hz),7.36-7.46 (3H, m), 7.81-7.91 (1H, m), 8.39 (1H, d, J=5.8 Hz).

Synthetic Example 292-[Cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylethyl carbonate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.238 g) intetrahydrofuran was dropwise added pyridine (0.20 mL) under ice-cooling.After stirring under ice-cooling for 30 min., 2-(cyclohexylamino)ethylethyl carbonate hydrochloride (0.605 g) obtained in Reference Example 26was added. Triethylamine (0.335 mL) was dropwise added, and the mixturewas stirred at room temperature for 2 hrs. Ethyl acetate (50 mL) wasadded to the reaction mixture, and the mixture was washed with water (50mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), and(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.60 g), triethylamine (0.45 mL) and 4-dimethylaminopyridine (0.02 g)were added. The mixture was stirred at 60° C. for 24 hrs. Ethyl acetate(50 mL) was added to the reaction mixture, and the mixture was washedwith water (20 mL) and saturated brine (50 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by flash silica gel column chromatography (eluted with ethylacetate:hexane=1:4, then ethyl acetate) to give the title compound (0.92g) as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.02-2.27 (16H, m), 3.40-4.60 (9H, m), 4.78 (1H×0.5, d,J=13.2 Hz), 4.97 (2H×0.5,s), 5.44 (1H×0.5, d, J=13.2 Hz), 6.69 (1H, d,J=5.6 Hz), 7.32-7.54 (3H, m), 7.80-7.91 (1H, m), 8.38 (1H, d, J=5.6 Hz).

Synthetic Example 252-[[[(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethylacetate

To a solution (350 mL) of bis(trichloromethyl)carbonate (13.4 g) intetrahydrofuran was dropwise added pyridine (10.38 mL) underice-cooling. After stirring under ice-cooling for 30 min.,2-anilinoethyl acetate hydrochloride (25.9 g) obtained in ReferenceExample 27 was added. Triethylamine (18.4 mL) was dropwise added, andthe mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, ethyl acetate (500 mL) and water(500 mL) were added to the residue, and the mixture was stirred. Theethyl acetate layer was separated and taken, washed with saturated brine(500 mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give 2-[(chlorocarbonyl)(phenyl)amino]ethyl acetate.This was dissolved in tetrahydrofuran (300 mL),(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(41.2 g), triethylamine (15.6 mL) and 4-dimethylaminopyridine (1.363 g)were added, and the mixture was stirred at 60° C. for 3 hrs. Ethylacetate (800 mL) was added to the reaction mixture, and the mixture waswashed twice with water (800 mL) and with saturated brine (800 mL),dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=3:7, then 1:1).Crystallization from diethyl ether gave the title compound (54.1 g) as awhite solid.

¹H-NMR(CDCl₃): 2.00 (3H, s), 2.25 (3H, s), 4.15-4.48 (6H, m), 4.83 (1H,d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 6.67 (1H, d, J=5.4 Hz),7.03-7.45 (8H, m), 7.64-7.69 (1H, m), 8.40 (1H, d, J=5.4 Hz).

Synthetic Example 262-[[[2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethylacetate

To a solution (10 mL) of 2-[(chlorocarbonyl)(phenyl)amino]ethyl acetate(0.58 g) prepared in the same manner as in Synthetic Example 25 intetrahydrofuran were added2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.739 g), triethylamine (0.558 mL) and 4-dimethylaminopyridine (0.024g), and the mixture was stirred at 60° C. for 15 hrs. Ethyl acetate (30mL) was added to the reaction mixture, and the mixture was washed withwater (50 mL) and saturated brine (50 mL), dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by flash silica gel column chromatography (eluted withacetone:hexane=1:4, then 3:2). Crystallization from diethyl ether gavethe title compound (0.779 g) as a white solid.

¹H-NMR(CDCl₃): 1.99 (3H, s), 2.25 (3H, s), 4.20-4.48 (6H, m), 4.83 (1H,d, J=13.6 Hz), 5.05 (1H, d, J=13.6 Hz), 6.67 (1H, d, J=5.8 Hz),7.03-7.45 (8H, m), 7.64-7.69 (1H, m), 8.40 (1H, d, J=5.8 Hz).

Synthetic Example 27

tert-Butyl[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]-3-pyridyl]methylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.30 g) intetrahydrofuran was dropwise added pyridine (0.24 mL) under ice-cooling.After stirring under ice-cooling for 30 min., tert-butyl[2-(methylamino)-3-pyridyl]methyl carbonate (0.71 g) obtained inReference Example 28 was added, and the mixture was stirred at roomtemperature for 2 hrs. The precipitated solid was filtered off and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL),(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.92 g), triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.031 g)were added, and the mixture was stirred at 60° C. for 1 hr. Water (50mL) was added to the reaction mixture and the mixture was extractedtwice with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (50 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashsilica gel column chromatography (eluted with acetone:hexane=1:2), andfurther by basic silica gel column chromatography (eluted with ethylacetate) to give the title compound (0.38 g) as a pale-yellow amorphoussolid.

¹H-NMR(CDCl₃): 1.46 (9H, s), 2.25 (3H, s), 3.54 (3H, s), 4.37 (2H, q,J=8.0 Hz), 4.95 (2H, s), 5.15 (1H, d, J=14.0 Hz), 5.27 (1H, d, J=14.0Hz), 6.63 (1H, d, J=5.4 Hz), 7.26-7.45 (3H, m), 7.69-7.87 (3H, m), 8.33(1H, d, J=5.4 Hz), 8.44-8.46 (1H, m).

Synthetic Example 282-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]benzylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (1.46 g) intetrahydrofuran was dropwise added pyridine (1.16 mL) under ice-cooling.After stirring under ice-cooling for 30 min., 2-(methylamino)benzylacetate (2.57 g) obtained in Reference Example 29 was added. The mixturewas stirred at room temperature for 3 hrs. The precipitated solid wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was dissolved in tetrahydrofuran (40 mL),(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(4.41 g), triethylamine (3.33 mL) and 4-dimethylaminopyridine (0.15 g)were added, and the mixture was stirred at 60° C. for 18 hrs. Water (100mL) was added to the reaction mixture, and the mixture was extractedwith ethyl acetate (100 mL). The ethyl acetate layer was washed withsaturated brine (100 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by flashsilica gel column chromatography (eluted with acetone:hexane=1:4, then1:2). Crystallization from ethyl acetate-diethyl ether-hexane gave thetitle compound (2.76 g) as a white solid.

¹H-NMR(CDCl₃): 2.10 (3H, s), 2.00-2.30 (3H, br), 3.20-3.50 (3H, br),4.38 (2H, q, J=7.6 Hz), 4.70-5.20 (2H, m), 5.20-5.50 (2H, m), 6.65 (1H,d, J=5.4 Hz), 7.10-7.82 (8H, m), 8.38 (1H, d, J=5.4 Hz).

Synthetic Example 292-[[2-(Acetyloxy)ethyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., 2-[(2-acetyloxyethyl)amino]ethyl acetatehydrochloride (1.13 g) obtained in Reference Example 30 was added. Asolution (1 mL) of triethylamine (0.70 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2hrs. The precipitated solid was filtered off and the filtrate wasconcentrated under reduced pressure. Ethyl acetate (20 mL) was added tothe residue, the precipitated solid was filtered off and the filtratewas concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.48 g), triethylamine (1.12 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue. The mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (50 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:1, then ethyl acetate), and furtherby basic silica gel column chromatography (eluted with ethylacetate:hexane=1:1, then ethyl acetate). The resulting product wasdissolved in ethyl acetate (20 mL), activated carbon was added and themixture was stirred overnight. The activated carbon was filtered off andthe filtrate was concentrated under reduced pressure to give the titlecompound (1.60 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 2.06 (3H, s), 2.08 (3H, s), 2.24 (3H, s), 3.40-4.45 (8H,m), 4.39 (2H, q, J=7.9 Hz), 4.88 (1H, d, J=13.2 Hz), 5.05 (1H, d, J=13.2Hz), 6.66 (1H, d, J=5.6 Hz), 7.38-7.50 (3H, m), 7.87 (1H, d, J=6.9 Hz),8.36 (1H, d, J=5.6 Hz).

Synthetic Example 30[(2S)-1-[[(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]-2-pyrrolidinyl]methylacetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., (S)-2-pyrrolidinylmethyl acetate hydrochloride(0.90 g) obtained in Reference Example 31 was added. A solution (1 mL)of triethylamine (0.70 mL) in tetrahydrofuran was dropwise added, andthe mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 1 day and at roomtemperature for 2 days. After concentration under reduced pressure,water (50 mL) was added to the residue and the mixture was extractedwith ethyl acetate (50 mL). The ethyl acetate layer was washed withsaturated brine (50 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=1:1, then ethyl acetate) and further by silica gel columnchromatography (eluted with ethyl acetate:hexane=3:1, then ethylacetate, then acetone:ethyl acetate=1:4, then 2:3) to give the titlecompound (0.80 g) as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.80-2.30 (4H, m), 2.09 (3H, s), 2.30 (3H, s), 3.39 (1H,m), 3.50-3.62 (1H, m), 4.20-4.45 (4H, m), 4.58 (1H, m), 4.89 (1H, d,J=13.5 Hz), 4.96 (1H, d, J=13.5 Hz), 6.65 (1H, d, J=5.9 Hz), 7.36-7.48(3H, m), 7.89 (1H, d, J=8.7 Hz), 8.38 (1H, d, J=5.9 Hz).

Synthetic Example 31 Ethyl[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]acetate

To a solution (30 mL) of bis(trichloromethyl)carbonate (0.50 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.40mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., sarcosine ethyl ester hydrochloride (0.77 g)was added. A solution (1 mL) of triethylamine (0.70 mL) intetrahydrofuran was dropwise added and the mixture was stirred at roomtemperature for 1 hr. The precipitated solid was filtered off and thefiltrate was concentrated under reduced pressure. Water (50 mL) wasadded to the residue, and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with saturated brine (50 mL)and dried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (33 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazolesodium (1.37 g) and 4-dimethylaminopyridine (catalytic amount) wereadded, and the mixture was stirred at 60° C. overnight. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (50 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then ethylacetate) to give the title compound (0.40 g) as a yellow amorphoussolid.

¹H-NMR(CDCl₃): 1.33 (3H, t, J=7.1 Hz), 2.24 (3H, s), 3.10 (3H, bs),3.70-4.30 (2H, br), 4.28 (2H, q, J=7.1 Hz), 4.38 (2H, q, J=7.8 Hz),4.82-5.10 (2H, br), 6.63 (1H, d, J=5.5 Hz), 7.34-7.52 (2H, m), 7.70-7.90(2H, m), 8.32 (1H, d, J=5.5 Hz).

Synthetic Example 322-[[[5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethylbenzoate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.344 g) intetrahydrofuran was dropwise added a solution (5 mL) of pyridine (0.281mL) in tetrahydrofuran under ice-cooling, and the mixture was stirred at0° C. for 30 min. 2-(Methylamino)ethyl benzoate hydrochloride (0.750 g)obtained in Reference Example 5 was added. A solution (5 mL) oftriethylamine (0.485 mL) in tetrahydrofuran was added, and the mixturewas stirred at 0° C. for 1 hr. and at room temperature for 30 min. Thereaction mixture was concentrated under reduced pressure and water (30mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(30 mL), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained oil was dissolved in tetrahydrofuran (5mL), added to a solution (10 mL) of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazole(1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g)in tetrahydrofuran, and the mixture was stirred at 40° C. for 18 hrs.The reaction mixture was concentrated under reduced pressure and water(30 mL) was added to the residue. The mixture was extracted with ethylacetate (50 mL). The ethyl acetate layer was washed with saturated brine(30 mL), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1, then ethylacetate) to give a 1:1 mixture (1.50 g) of the title compound and2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethylbenzoate as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 2.05-2.35 (6H, m), 3.00-3.30 (3H, br), 3.60-4.40 (8H, m),4.60-5.10 (4H, m), 6.80-7.00 (2H, m), 7.20-7.70 (4H, m), 7.95-8.25 (3H,m).

Synthetic Example 333-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propylbenzoate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., 3-(methylamino)propyl benzoate hydrochloride(1.38 g) obtained in Reference Example 32 was added. A solution (1 mL)of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, andthe mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (25 mL) and driedover anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.63 g), triethylamine (1.23 mL) and 4-dimethylaminopyridine (0.054 g)were added, and the mixture was stirred at 60° C. for 4 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (1.26 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 2.21 (3H, s), 2.20-2.30 (2H,bm), 3.06 (3H, bs), 3.60-3.75(2H,bm), 4.36 (2H, q, J=7.8 Hz), 4.30-4.50 (2H,bm), 4.80-5.15 (2H,bm),6.62 (1H, d, J=5.7 Hz), 7.26-7.44 (5H, m), 7.54 (1H, m), 7.81 (1H, m),7.93-8.03 (2H,bm), 8.35 (1H, d, J=5.7 Hz).

Synthetic Example 342-[Methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyltetrahydropyran-4-yl carbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 20 min., 2-(methylamino)ethyl tetrahydropyran-4-ylcarbonate hydrochloride (1.43 g) obtained in Reference Example 17 wasadded. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuranwas dropwise added, and the mixture was stirred at room temperature for3 hrs. After concentration under reduced pressure, water (30 mL) wasadded to the residue, and the mixture was extracted with ethyl acetate(80 mL). The ethyl acetate layer was washed with saturated brine (20mL), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.63 g), triethylamine (1.23 mL) and 4-dimethylaminopyridine (0.027 g)were added, and the mixture was stirred at 60° C. for 17.5 hrs. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (120 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1), then bysilica gel column chromatography (eluted with ethyl acetate:hexane=1:1,then 2:1). Crystallization from diethyl ether gave the title compound(1.23 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.10(3H, bs), 3.40-4.30 (2H, br), 3.46-3.59 (2H, m), 3.87-3.99 (2H, m), 4.39(2H, q, J=7.9 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.65 (1H, d, J=5.4Hz), 7.35-7.50 (3H, m), 7.85 (1H, m), 8.36 (1H, d, J=5.4 Hz).

Synthetic Example 35 Ethyl2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 2-(methylamino)ethyl carbonatehydrochloride (1.10 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (30 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (80mL). The ethyl acetate layer was washed with saturated brine (30 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.63 g), triethylamine (1.23 mL), 4-dimethylaminopyridine (0.054 g) wasadded, and the mixture was stirred at 60° C. for 14 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with saturated brine (30 mL), and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1), andthen by silica gel column chromatography (eluted with ethylacetate:hexane=1:1, then 2:1) to give the title compound (1.27 g) as ayellow amorphous solid.

¹H-NMR(CDCl₃): 1.32 (3H, t, J=7.1 Hz), 2.23 (3H, s), 3.09 (3H, bs),3.50-4.76 (4H, br), 4.21 (2H, q, J=7.1 Hz), 4.38 (2H, q, J=7.9 Hz),4.84-5.14 (2H, m), 6.64 (1H, d, J=5.6 Hz), 7.36-7.46 (3H, m), 7.83 (1H,d, J=7.2 Hz), 8.34 (1H, d, J=5.6 Hz).

Synthetic Example 36 Ethyl2-[methyl[[(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., ethyl 2-(methylamino)ethyl carbonatehydrochloride (1.10 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2hrs. After concentration under reduced pressure, water (30 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (80mL). The ethyl acetate layer was washed with saturated brine (30 mL),and dried over anhydrous magnesium sulfate. The layer was concentratedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(20 mL).(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.15 g), triethylamine (0.87 mL) and 4-dimethylaminopyridine (0.035 g)were added, and the mixture was stirred at 60° C. for 12 hrs. Afterconcentration under reduced pressure, water (30 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with saturated brine (30 mL), and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1).Crystallization from diethyl ether gave the title compound (0.40 g) as acolorless solid.

¹H-NMR(CDCl₃): 1.32 (3H, t, J=7.2 Hz), 2.23 (3H, s), 3.10 (3H, bs),3.50-4.56 (4H, br), 4.22 (2H, q, J=7.2 Hz), 4.38 (2H, q, J=7.9 Hz),4.84-5.14 (2H, m), 6.65 (1H, d, J=5.6 Hz), 7.34-7.50 (3H, m), 7.85 (1H,m), 8.36 (1H, d, J=5.6 Hz).

Synthetic Example 37 Ethyl2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 2-(methylamino)ethyl carbonatehydrochloride (1.10 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2.5hrs. After concentration under reduced pressure, water (30 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (80mL). The ethyl acetate layer was washed with saturated brine (30 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine(1.44 g) synthesized by the method described in JP-A-63-146882,triethylamine (1.16 mL) and 4-dimethylaminopyridine (0.049 g) wereadded, and the mixture was stirred at 60° C. for 6 hrs. Afterconcentration under reduced pressure, water (30 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1).Crystallization from diethyl ether gave the title compound (0.721 g) asa colorless solid.

¹H-NMR(CDCl₃): 1.25-1.34 (3H, m), 2.23 (6H, s), 3.15, 3.32 (total 3H,s), 3.72 (3H, s), 3.90-4.53 (9H, m), 4.86 (1H, d, J=13.4 Hz), 4.95 (1H,d, J=13.4 Hz), 6.79 (1H, d, J=8.7 Hz), 7.95 (1H, d, J=8.7 Hz), 8.22 (1H,s).

Synthetic Example 382-[[[5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethylacetate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl acetate hydrochloride(0.922 g) obtained in Reference Example 2 was added. A solution (1 mL)of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, andthe mixture was stirred at room temperature for 2 hrs. Afterconcentration under reduced pressure, water (30 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was dissolved in tetrahydrofuran (10 mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine(0.85 g) synthesized by the method described in JP-A-63-146882,triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.025 g) wereadded, and the mixture was stirred at 60° C. for 5 hrs. Afterconcentration under reduced pressure, water (30 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (90 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1).Crystallization from diethyl ether gave the title compound (0.173 g) asa colorless solid.

¹H-NMR(CDCl₃): 2.04, 2.09 (total 3H, s), 2.24 (6H, s), 3.13, 3.30 (total3H, s), 3.45-3.97 (2H, m), 3.72 (3H, s), 3.97 (3H, s), 4.15-4.50 (2H,m), 4.85 (1H, d, J=13.1 Hz), 4.96 (1H, d, J=13.1 Hz), 6.80 (1H, d, J=8.9Hz), 7.96 (1H, d, J=8.9 Hz), 8.22 (1H, s).

Synthetic Example 392-[[[5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](phenyl)amino]ethylacetate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-anilinoethyl acetate hydrochloride (0.647 g)obtained in Reference Example 27 was added. A solution (1 mL) oftriethylamine (0.419 mL) in tetrahydrofuran was dropwise added, and themixture was stirred at room temperature for 3 hrs. After concentrationunder reduced pressure, water (20 mL) was added to the residue, and themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (15 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was dissolved in tetrahydrofuran (10 mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine(0.867 g) synthesized by the method described in JP-A-63-146882,triethylamine (0.697 mL) and 4-dimethylaminopyridine (0.020 g) wasadded, and the mixture was stirred at 60° C. for 10 hrs. Afterconcentration under reduced pressure, water (20 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (15 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:1). Crystallizationfrom diethyl ether gave the title compound (0.311 g) as a colorlesssolid.

¹H-NMR(CDCl₃): 1.96 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 3.72 (3H, s),4.01 (3H, s), 4.12-4.52 (4H, m), 4.78-5.22 (2H, m), 6.62 (1H, d, J=8.7Hz), 7.02-7.18 (3H, m), 7.32-7.48 (2H, m), 7.73 (1H, d, J=8.7 Hz), 8.26(1H, s).

Synthetic Example 404-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]butylacetate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 4-(methylamino)butyl acetate hydrochloride(1.08 g) obtained in Reference Example 37 was added. A solution (1 mL)of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, andthe mixture was stirred at room temperature for 3 hrs. Afterconcentration under reduced pressure, water (50 mL) was added to theresidue and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (50 mL) and driedover anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.02 g), triethylamine (0.77 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (0.93 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.65-1.85 (4H, m), 2.03 (3H, s), 2.23 (3H, s), 3.02 (3H,bs), 3.45-3.63 (2H, m), 4.03-4.13 (2H, m), 4.37 (2H, q, J=7.8 Hz),4.85-5.13 (2H, m), 6.64 (1H, d, J=5.6 Hz), 7.36-7.46 (3H, m), 7.84 (1H,d, J=8.4 Hz), 8.35 (1H, d, J=5.6 Hz).

Synthetic Example 41 Ethyl4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]butylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 4-(methylamino)butyl carbonatehydrochloride (1.27 g) obtained in Reference Example 39 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (50 mL) was addedto the residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.26 g), triethylamine (0.95 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2; then 1:1) to givethe title compound (1.08 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.31 (3H, t, J=7.2 Hz), 1.73-1.91 (4H, m), 2.23 (3H, s),3.01 (3H, bs), 3.50-3.62 (2H, m), 4.15-4.22 (4H, m), 4.38 (2H, q, J=7.8Hz), 4.87-5.13 (2H, m), 6.64 (1H, d, J=5.4 Hz), 7:35-7.46 (3H, m), 7.83(1H, d, J=7.8 Hz), 8.35 (1H, d, J=5.4 Hz).

Synthetic Example 42 Ethyl3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 3-(methylamino)propyl carbonatehydrochloride (1.18 g) obtained in Reference Example 44 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (50 mL) was addedto the residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.10 g), triethylamine (0.83 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (0.88 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.29 (3H, t, J=7.2 Hz), 2.10-2.20 (2H, m), 2.22 (3H, s),3.02 (3H, bs), 3.55-3.77 (2H, m), 4.14-4.30 (4H, m), 4.37 (2H, q, J=7.8Hz), 4.83-5.13 (2H, m), 6.64 (1H, d, J=5.6 Hz), 7.35-7.46 (3H, m), 7.82(1H, d, J=8.1 Hz), 8.35 (1H, d, J=5.6 Hz).

Synthetic Example 433-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propylacetate

To a solution (40 mL) of bis(trichloromethyl)carbonate (1.19 g) intetrahydrofuran was dropwise added a solution (2 mL) of pyridine (0.95mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 3-(methylamino)propyl acetate hydrochloride(1.90 g) obtained in Reference Example 42 was added. A solution (2 mL)of triethylamine (1.68 mL) in tetrahydrofuran was dropwise added, andthe mixture was stirred at room temperature for 3 hrs. Afterconcentration under reduced pressure, water (100 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (100 mL). Theethyl acetate layer was washed with saturated brine (100 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was dissolved in tetrahydrofuran (40 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.99 g), triethylamine (1.50 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (100 mL) was added tothe residue, and the mixture was extracted with ethyl acetate (100 mL).The ethyl acetate layer was washed with saturated brine (100 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (1.22 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.97 (3H, s), 2.05-2.15 (2H, m), 2.22 (3H, s), 3.03 (3H,bs), 3.42-3.72 (2H, m), 4.10-4.22 (2H, m), 4.37 (2H, q, J=7.8 Hz),4.85-5.13 (2H, m), 6.64 (1H, d, J=5.6 Hz), 7.24-7.44 (3H, m), 7.83 (1H,d, J=7.5 Hz), 8.35 (1H, d, J=5.6 Hz).

Synthetic Example 443-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propane-1,2-diyldiacetate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 3-(methylamino)propane-1,2-diyl diacetatehydrochloride (1.35 g) obtained in Reference Example 46 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (50 mL) was addedto the residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.27 g), triethylamine (0.96 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (0.64 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 2.05 (3H, s), 2.13 (3H, s), 2.23 (3H, s), 3.07 (3H, bs),3.42-3.95 (2H, m), 4.06-4.43 (2H, m), 4.38 (2H, q, J=7.8 Hz), 4.85-5.05(2H, m), 5.42-5.50 (1H, m), 6.63-6.66 (1H, m), 7.38-7.51 (3H, m),7.78-7.85 (1H, m), 8.33-8.36 (1H, m).

Synthetic Example 45 Diethyl3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]propane-1,2-diylbiscarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., diethyl 3-(methylamino)propane-1,2-diylbiscarbonate hydrochloride (1.71 g) obtained in Reference Example 47 wasadded. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuranwas dropwise added, and the mixture was stirred at room temperature for3 hrs. After concentration under reduced pressure, water (50 mL) wasadded to the residue and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with saturated brine (50 mL)and dried over anhydrous magnesium sulfate. The layer was concentratedunder reduced pressure, and the residue was dissolved in tetrahydrofuran(20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.53 g), triethylamine (1.16 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (1.42 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.28-1.34 (6H, m), 2.22 (3H, s), 3.07 (3H, bs), 3.42-4.60(10H, m), 4.85-5.08 (2H, m), 5.30-5.42 (1H, m), 6.62-6.64 (1H, m),7.37-7.42 (3H, m), 7.80-7.83 (1H, m), 8.32-8.35 (1H, m).

Synthetic Example 462-[[[5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl3-chlorobenzoate

To a solution (7 mL) of bis(trichloromethyl)carbonate (0.194 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.162mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-(methylamino)ethyl 3-chlorobenzoatehydrochloride (0.50 g) obtained in Reference Example 7 was added. Asolution (1 mL) of triethylamine (0.279 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2.5hrs. After concentration under reduced pressure, water (15 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (50mL). The ethyl acetate layer was washed with saturated brine (15 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (10 mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine(0.445 g) synthesized by the method described in JP-A-63-146882,triethylamine (0.357 mL) and 4-dimethylaminopyridine (0.012 g) wereadded, and the mixture was stirred at 60° C. for 14 hrs. Afterconcentration under reduced pressure, water (30 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (70 mL). Theethyl acetate layer was washed with saturated brine (20 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (0.360 g) as a colorless amorphous solid.

¹H-NMR(CDCl₃): 2.21 (3H, s), 2.23 (3H, s), 3.32, 3.38 (total 3H, s),3.72 (3H, s), 3.81 (3H, s), 3.92-4.09 (2H, m), 4.50-4.73 (2H, m), 4.87(1H, d, J=13.4 Hz), 4.94 (1H, d, J=13.4 Hz), 6.77 (1H, d, J=8.8 Hz),7.36 (1H, m), 7.52 (1H, m), 7.80-8.03 (3H, m) 8.20 (1H, s).

Synthetic Example 472-[Methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.582 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.485mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., 2-(methylamino)ethyl acetate hydrochloride (0.922g) obtained in Reference Example 2 was added. A solution (1 mL) oftriethylamine (0.84 mL) in tetrahydrofuran was dropwise added, and themixture was stirred at room temperature for 2.5 hrs. After concentrationunder reduced pressure, water (40 mL) was added to the residue, and themixture was extracted with ethyl acetate (80 mL). The ethyl acetatelayer was washed with saturated brine (25 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was dissolved in tetrahydrofuran (15 mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.10 g), triethylamine (0.84 mL) and 4-dimethylaminopyridine (0.036 g)were added, and the mixture was stirred at 60° C. for 4.5 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (30 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by silica gel column chromatography(eluted with ethyl acetate:hexane=1:1, then 2:1) to give the titlecompound (1.18 g) as a colorless solid.

¹H-NMR(CDCl₃): 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H,br), 4.25-4.50 (2H, m), 4.38 (2H, q, J=7.8 Hz), 4.84-5.18 (2H, m), 6.64(1H, d, J=5.6 Hz), 7.36-7.48 (3H, m), 7.85 (1H, d, J=7.8 Hz), 8.35 (1H,d, J=5.6 Hz).

Synthetic Example 48 Ethyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

A solution of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(130 g), triethylamine (63.8 mL), 4-dimethylaminopyridine (0.86 g) and2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (84.8 g) obtainedin Reference Example 34 in tetrahydrofuran (813 mL) was stirred at45-50° C. for 18 hrs. The reaction mixture was concentrated underreduced pressure and water (300 mL) was added to the residue, and themixture was extracted with ethyl acetate (700 mL). The ethyl acetatelayer was washed 3 times with saturated brine (300 mL), and anhydrousmagnesium sulfate (130 g) and activated carbon (13 g) were added. Themixture was stirred at room temperature for 30 min. and filtrated. Thefiltrate was concentrated under reduced pressure and the residue wasdissolved in diethyl ether (600 mL) containing triethylamine (0.49 mL),and the mixture was concentrated under reduced pressure. This step wasfurther repeated twice. The obtained oily substance was dissolved inethanol (200 mL) containing triethylamine (2.45 mL) and water (120 mL)was dropwise added under ice-cooling. The precipitated crystals werecollected by filtration, washed 3 times with ice-cooled ethanol-water(volume ratio 1:1, 150 mL) and dried to give the title compound (172.2g) as a colorless solid. ¹H-NMR(CDCl₃) showed the same chart as with thecompound obtained in Synthetic Example 14.

Synthetic Example 49 2-Ethoxyethyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.43 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.35mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 10 min., 2-ethoxyethyl 2-(methylamino)ethyl carbonatehydrochloride (0.82 g) obtained in Reference. Example 48 was added. Asolution (1 mL) of triethylamine (0.60 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3days. After concentration under reduced pressure, water (50 mL) wasadded to the residue and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid(20 mL) and saturated brine (50 mL) and dried over anhydrous magnesiumsulfate. The layer was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 11 hrs. After concentration under reduced pressure,water (50 mL) was added to the residue and the mixture was extractedwith ethyl acetate (50 mL). The ethyl acetate layer was washed withsaturated brine (50 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=3:7, then ethyl acetate:hexane=7:3) to give the titlecompound (1.39 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.19 (3H, t, J=6.9 Hz), 2.23 (3H, s), 3.09 (3H, bs),3.40-4.20 (2H, br), 3.53 (2H, q, J=6.9 Hz), 3.63-3.69 (2H, m), 4.27-4.34(2H, m), 4.39 (2H, q, J=7.8 Hz), 4.47 (2H, m), 4.80-5.20 (2H, m), 6.65(1H, d, J=5.6 Hz), 7.30-7.52 (3H, m), 7.84 (1H, d, J=7.5 Hz), 8.35 (1H,d, J=5.6 Hz).

Synthetic Example 50 3-Methoxypropyl2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.53 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.44mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 5 min., 3-methoxypropyl 2-(methylamino)ethyl carbonatehydrochloride (0.82 g) obtained in Reference Example 49 was added. Asolution (1 mL) of triethylamine (0.75 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 1 hr.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL)and saturated brine (50 mL) and dried over anhydrous magnesium sulfate.The layer was concentrated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 6 hrs. After concentration under reduced pressure, water(50 mL) was added to the residue and the mixture was extracted withethyl acetate (50 mL). The ethyl acetate layer was washed with saturatedbrine (50 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by basicsilica gel column chromatography (eluted with ethyl acetate:hexane=3:7,then ethyl acetate:hexane=7:3). Crystallization from diethyl ether gavethe title compound (0.70 g) as a colorless solid.

¹H-NMR(CDCl₃): 1.94 (2H,quintet, J=6.2 Hz), 2.23 (3H, s), 3.09 (3H, bs),3.31 (3H, s), 3.40-4.20 (2H, br), 3.44 (2H, t, J=6.2 Hz), 4.25 (2H, t,J=6.5 Hz), 4.38 (2H, q, J=7.8 Hz), 4.44 (2H, m), 4.80-5.20 (2H, m), 6.64(1H, d, J=5.6 Hz), 7.35-7.48 (3H, m), 7.83 (1H, d, J=7.8 Hz), 8.34 (1H,d, J=5.6 Hz).

Synthetic Example 512-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylN,N-dimethylglycinate

2-(Methylamino)ethyl N,N-dimethylglycinate dihydrochloride (1.06 g)obtained in Reference Example 50 was added to tetrahydrofuran (40 mL)and the mixture was stirred for a while, to whichbis(trichloromethyl)carbonate (0.77 g) was added. After ice-cooling, asolution (5 mL) of triethylamine (2.17 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 3hrs. The precipitated solid was filtered off and ethyl acetate (80 mL)was added. The mixture was washed with an ice-cooled aqueous sodiumhydrogen carbonate solution (50 mL) and saturated brine (50 mL×2) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 3 days. 4-Dimethylaminopyridine (0.037 g) was added, andthe mixture was further stirred at 60° C. for 6 hrs. After concentrationunder reduced pressure, an aqueous sodium hydrogen carbonate solution(50 mL) was added to the residue, and the mixture was extracted withethyl acetate (50 mL). The ethyl acetate layer was washed With saturatedbrine (50 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by basicsilica gel column chromatography (eluted with ethyl acetate:hexane=1:1,then ethyl acetate, then methanol:ethyl acetate=1:19). Crystallizationfrom diethyl ether gave the title compound (0.41 g) as a colorlesssolid.

¹H-NMR(CDCl₃): 2.23 (3H, s), 2.35 (6H, s), 3.08 (3H, bs), 3.21 (2H, s),3.50-4.20 (2H, br), 4.38 (2H, q, J=7.8 Hz), 4.44 (2H, m), 4.80-5.18 (2H,m), 6.64 (1H, d, J=5.6 Hz), 7.36-7.48 (3H, m), 7.84 (1H, d, J=6.9 Hz),8.35 (1H, d, J=5.6 Hz).

Synthetic Example 52S-[2-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl]thioacetate

S-[2-(Methylamino)ethyl]thioacetate hydrochloride (0.75 g) obtained inReference Example 51 was added to tetrahydrofuran (30 mL) and themixture was stirred for a while, to which bis(trichloromethyl)carbonate(0.66 g) was added. After ice-cooling, a solution (10 mL) oftriethylamine (1.85 mL) in tetrahydrofuran was dropwise added and themixture was stirred under ice-cooling for 30 min. and at roomtemperature for 30 min. The precipitated solid was filtered off andethyl acetate (50 mL) was added to the filtrate. The mixture was washedwith ice-cooled 0.2N hydrochloric acid (20 mL) and saturated brine (50mL) and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.96 g), triethylamine (0.54 mL) and 4-dimethylaminopyridine (0.032 g)were added, and the mixture was stirred at 60° C. for 6 hrs. and at roomtemperature for 8 hrs. After concentration under reduced pressure, water(50 mL) was added to the residue and the mixture was extracted withethyl acetate (50 mL). The ethyl acetate layer was washed with saturatedbrine (50 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography (eluted with acetone:hexane=3:7, thenacetone:hexane=7:3) to give the title compound (1.19 g) as a yellowamorphous solid.

¹H-NMR(CDCl₃): 2.23 (3H, s), 2.34 (3H, s), 3.10 (3H, bs), 3.22 (2H, t,J=6.6 Hz), 3.67 (2H, m), 4.38 (2H, q, J=7.8 Hz), 4.80-5.20 (2H, m), 6.64(1H, d, J=5.7 Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J=6.9 Hz), 8.35 (1H,d, J=5.7 Hz).

Synthetic Example 53 Ethyl2-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethoxy]ethylcarbonate

To a solution (40 mL) of bis(trichloromethyl)carbonate (1.19 g) intetrahydrofuran was dropwise added a solution (2 mL) of pyridine (0.95mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 2-[2-(methylamino)ethoxy]ethyl carbonatehydrochloride (2.73 g) obtained in Reference Example 52 was added. Asolution (2 mL) of triethylamine (1.68 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (100 mL) wasadded to the residue, and the mixture was extracted with ethyl acetate(100 mL). The ethyl acetate layer was washed with saturated brine (100mL) and dried over anhydrous magnesium sulfate. After concentrationunder reduced pressure, the residue was dissolved in tetrahydrofuran (40mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(2.80 g), triethylamine (2.11 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (100 mL) was added tothe residue, and the mixture was extracted with ethyl acetate (100 mL).The ethyl acetate layer was washed with saturated brine (100 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (2.19 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.28 (3H, t, J=7.2 Hz), 2.24 (3H, s), 3.10 (3H, bs),3.38-3.80 (6H, m), 4.18 (2H, q, J=7.2 Hz), 4.27-4.34 (2H, m), 4.38 (2H,q, J=8.4 Hz), 4.83-5.30 (2H, m), 6.65 (1H, d, J=5.7 Hz), 7.35-7.50 (3H,m), 7.84 (1H, d, J=7.8 Hz), 8.36 (1H, d, J=5.7 Hz).

Synthetic Example 54 Ethyl2-[methyl[[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethoxy]carbonyl]amino]ethylcarbonate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl2-[methyl[[2-(methylamino)ethoxy]carbonyl]amino]ethyl carbonatehydrochloride (1.71 g) obtained in Reference Example 53 was added. Asolution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (50 mL) was addedto the residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. The layer was concentrated underreduced pressure, and the residue was dissolved in tetrahydrofuran (20mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.59 g), triethylamine (1.20 mL) and 4-dimethylaminopyridine (catalyticamount) were added, and the mixture was stirred at 60° C. overnight.After concentration under reduced pressure, water (50 mL) was added tothe residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with saturated brine (50 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givethe title compound (1.62 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.24-1.31 (3H, m), 2.24 (3H, bs), 2.97-2.99 (3H, m), 3.10(3H, bs), 3.55-3.58 (2H, m), 4.09-4.50 (10H, m), 4.88-5.08 (2H, m), 6.65(1H, t, J=5.7 Hz), 7.36-7.48 (3H, m), 7.85 (1H, d, J=6.9 Hz), 8.36 (1H,d, J=5.7 Hz).

Synthetic Example 55 Ethyl2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylcarbonate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., ethyl 2-(methylamino)ethyl carbonatehydrochloride (0.551 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.418 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2hrs. After concentration under reduced pressure, water (15 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (50mL). The ethyl acetate layer was washed with saturated brine (15 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (10 mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole(0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012g) were added, and the mixture was stirred at 60° C. for 12 hrs. Afterconcentration under reduced pressure, water (20 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (15 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givea 3:2 mixture (0.92 g) of the title compound and ethyl2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylcarbonate as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.27-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s),2.99-3.23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s),3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m),4.82-5.06 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J=9.0 Hz), 7.66(1H, m), 8.21 (1H, s).

Synthetic Example 562-[[[5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethylacetate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-anilinoethyl acetate hydrochloride (0.647 g)obtained in Reference Example 27 was added. A solution (1 mL) oftriethylamine (0.419 mL) in tetrahydrofuran was dropwise added, and themixture was stirred at room temperature for 3 hrs. After concentrationunder reduced pressure, water (20 mL) was added to the residue, and themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (15 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was dissolved in tetrahydrofuran (10 mL).5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole(0.829 g), triethylamine (0.669 mL) and 4-dimethylaminopyridine (0.012g) were added, and the mixture was stirred at 60° C. for 14 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (15 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2) to give a 1:1mixture (1.10 g) of the title compound and2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethylacetate as a colorless amorphous solid.

¹H-NMR(CDCl₃): 1.99 (3H, s), 2.19 (1.5H.s), 2.21 (1.5H, s), 2.25 (3H,s), 3.70 (1.5H, s), 3.71 (3H, s), 3.78 (1.5H, s), 3.84 (1.5H, s),4.15-4.56 (4H, m), 4.74-4.80 (1H, m), 4.91-4.98 (1H, m), 6.83-6.91(1.5H, m), 7.04-7.19 (3.5H, m), 7.25-7.53 (2.5H, m), 7.51 (0.5H, d,J=8.7 Hz), 8.25 (1H, s).

Synthetic Example 57 Ethyl2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylcarbonate

To a solution (10 mL) of(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole(1.34 g) synthesized by the method described in Synthetic Example 1 ofJapanese Patent Application under PCT laid-open under kohyo No.10-504290 in tetrahydrofuran were added2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtainedin Reference Example 34, triethylamine (1.08 mL) and4-dimethylaminopyridine (0.010 g), and the mixture was stirred at 60° C.for 6 hrs. After concentration under reduced pressure, water (30 mL) wasadded to the residue and the mixture was extracted with ethyl acetate(50 mL). The ethyl acetate layer was washed with saturated brine (15 mL)and dried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to givea 3:2 mixture (0.92 g) of the title compound and ethyl2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylcarbonate as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.25-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s),2.99-3.23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s),3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m),4.79-5.05 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J=9.3 Hz), 7.65(1H, m), 8.21 (1H, s)

Synthetic Example 58 Ethyl2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylcarbonate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., ethyl 2-(methylamino)ethyl carbonatehydrochloride (0.551 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.418 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 2.5hrs. After concentration under reduced pressure, water (15 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (50mL). The ethyl acetate layer was washed with saturated brine (15 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (10 mL).2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.723 g), triethylamine (0.528 mL) and 4-dimethylaminopyridine (0.012g) were added, and the mixture was stirred at 60° C. for 17 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (15 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2), then by silicagel column chromatography (eluted with ethyl acetate:hexane=1:1, thenethyl acetate) to give the title compound (0.44 g) as a colorlessamorphous solid.

¹H-NMR(CDCl₃): 1.31 (3H, t, J=7.1 Hz), 2.05 (2H, m), 2.18 (3H, s), 3.08(3H, bs), 3.34 (3H, s), 3.54 (2H, t, J=6.1 Hz), 3.61-4.01 (2H, m), 4.08(2H, t, J=6.3 Hz), 4.21 (2H, t, J=7.1 Hz), 4.38-4.54 (2H, m), 4.81-5.12(2H, m), 6.68 (1H, d, J=5.6 Hz), 7.34-7.48 (3H, m), 7.83 (1H, d, J=7.8Hz), 8.27 (1H, d, J=5.6 Hz).

Synthetic Example 592-[[[2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethylacetate

To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 30 min., 2-anilinoethyl acetate hydrochloride (0.647 g)obtained in Reference Example 27 was added. A solution (1 mL) oftriethylamine (0.419 mL) in tetrahydrofuran was dropwise added, and themixture was stirred at room temperature for 3 hrs. After concentrationunder reduced pressure, water (20 mL) was added to the residue, and themixture was extracted with ethyl acetate (50 mL). The ethyl acetatelayer was washed with saturated brine (15 mL) and dried over anhydrousmagnesium sulfate. After concentration under reduced pressure, theresidue was dissolved in tetrahydrofuran (10 mL).2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.877 g), triethylamine (0.641 mL) and 4-dimethylaminopyridine (0.012g) were added, and the mixture was stirred at 60° C. for 16 hrs. Afterconcentration under reduced pressure, water (40 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (80 mL). Theethyl acetate layer was washed with saturated brine (15 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2), then by silicagel column chromatography (eluted with ethyl acetate) to give the titlecompound (0.93 g) as a colorless amorphous solid.

¹H-NMR(CDCl₃): 1.99 (3H, s), 2.07 (3H.s), 2.19 (3H, s), 3.35 (3H, s),3.54 (2H, t, J=6.2 Hz), 4.09 (2H, t, J=6.2 Hz), 4.14-4.40 (4H, m), 4.80(1H, d, J=13.7 Hz), 5.00 (1H, d, J=13.7 Hz), 6.71 (1H, d, J=5.7 Hz),7.03-7.34 (7H, m), 7.38 (1H, m), 7.65 (1H, m), 8.32 (1H, d, J=5.7 Hz).

Synthetic Example 602-[[[5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethylethyl carbonate

To a solution (8 mL) of bis(trichloromethyl)carbonate (0.174 g) intetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.146mL) in tetrahydrofuran under ice-cooling. After stirring underice-cooling for 1 hr., ethyl 2-(methylamino)ethyl carbonatehydrochloride (0.330 g) obtained in Reference Example 14 was added. Asolution (1 mL) of triethylamine (0.250 mL) in tetrahydrofuran wasdropwise added, and the mixture was stirred at room temperature for 3hrs. After concentration under reduced pressure, water (10 mL) was addedto the residue, and the mixture was extracted with ethyl acetate (30mL). The ethyl acetate layer was washed with saturated brine (10 mL) anddried over anhydrous magnesium sulfate. After concentration underreduced pressure, the residue was dissolved in tetrahydrofuran (8 mL).5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole(0.432 g), triethylamine (0.279 mL) and 4-dimethylaminopyridine (0.008g) were added, and the mixture was stirred at 60° C. for 17.5 hrs. Afterconcentration under reduced pressure, water (20 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (10 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=1:2, then 1:1), then bysilica gel column chromatography (eluted with ethyl acetate:hexane=2:1,then ethyl acetate) to give a 1:1 mixture (0.09 g) of the title compoundand2-[[[6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]methylamino]ethylethyl carbonate as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.31 (3H, t, J=7.2 Hz), 3.06 (3H, s), 3.42-3.98 (2H, m),3.87 (3H, s), 3.90 (3H, s), 4.21 (2H, q, J=7.2 Hz), 4.36-4.54 (2H, m),4.90 (1H, d, J=13.2 Hz), 4.98 (1H, d, J=13.2 Hz), 6.54 (0.5H, t, J=73.5Hz), 6.61 (0.5H, t, J=73.5 Hz), 6.78 (1H, d, J=5.3 Hz), 7.15-7.25 (1.5H,m), 7.44 (0.5H, d, J=9.0 Hz), 7.59 (0.5H, s), 7.80 (0.5H, d, J=9.0 Hz),8.17 (1H, d, J=5.3 Hz).

Synthetic Example 612-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl1-methylpiperidine-4-carboxylate

2-(Methylamino)ethyl 1-methylpiperidine-4-carboxylate dihydrochloride(0.98 g) obtained in Reference Example 54 was added to tetrahydrofuran(50 mL) and the mixture was stirred for a while, to whichbis(trichloromethyl)carbonate (0.53 g) was added. After ice-cooling, asolution (50 mL) of triethylamine (2.01 mL) in tetrahydrofuran wasdropwise added and the mixture was stirred at room temperature for 3hrs. Ethyl acetate (100 mL) was added and the mixture was washed with anaqueous sodium hydrogen carbonate solution (100 mL) and saturated brine(80 mL) and dried over anhydrous magnesium sulfate. The layer wasconcentrated under reduced pressure, and the residue was dissolved intetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.74 g), triethylamine (0.56 mL) and 4-dimethylaminopyridine (0.049 g)were added, and the mixture was stirred at 60° C. overnight. Afterconcentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture wasextracted with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (50 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=7:3, then ethyl acetate, then methanol:ethylacetate=1:19) to give the title compound (0.78 g) as a yellow-greenamorphous solid.

¹H-NMR(CDCl₃): 1.65-2.05 (6H, m), 2.23 (3H, s), 2.25 (3H, s), 2.24-2.38(1H, m), 2.75-2.85 (2H, m), 3.07 (3H, bs), 3.40-4.10 (2H, br), 4.38 (2H,q, J=7.8 Hz), 4.40 (2H, m), 4.80-5.10 (2H, br), 6.64 (1H, d, J=5.6 Hz),7.36-7.47 (3H, m), 7.84 (1H, d, J=7.8 Hz), 8.35 (1H, d, J=5.6 Hz).

Synthetic Example 622-[[4-(Aminocarbonyl)phenyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (20 mL) of bis(trichloromethyl)carbonate (0.45 g) intetrahydrofuran was dropwise added a solution (10 mL) of2-[[4-(aminocarbonyl)phenyl]amino]ethyl acetate (0.67 g) obtained inReference Example 55 and triethylamine (0.63 mL) in tetrahydrofuranunder ice-cooling, and the mixture was stirred at room temperature for 1hr. After concentration under reduced pressure, water (50 mL) was addedto the residue and the mixture was extracted with ethyl acetate (50 mL).The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL)and saturated brine (50 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was dissolved intetrahydrofuran (30 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. for 30 min. and atroom temperature overnight. After concentration under reduced pressure,an aqueous sodium hydrogen carbonate solution (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with saturated brine (50 mL) and driedover anhydrous magnesium sulfate. After concentration under reducedpressure, the residue was purified by basic silica gel columnchromatography (eluted with ethyl acetate:hexane=4:6, then 6:4, then8:2) to give the title compound (1.26 g) as a yellow amorphous solid.

¹H-NMR(CDCl₃): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H,q, J=7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J=5.7 Hz), 7.26-7.38 (3H,m), 7.48 (2H, d, J=8.9 Hz), 7.54 (2H, d, J=8.9 Hz), 7.66-7.73 (1H, m),8.39 (1H, d, J=5.7 Hz).

Synthetic Example 632-[Methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl1-methyl-4-piperidinyl carbonate

2-(Methylamino)ethyl 1-methyl-4-piperidinyl carbonate dihydrochloride(1.01 g) obtained in Reference Example 56 was added to tetrahydrofuran(30 mL) and, after stirring for a while, ice-cooled.Bis(trichloromethyl)carbonate (0.69 g) was added and a solution (10 mL)of triethylamine (1.95 mL) in tetrahydrofuran was dropwise added. Afterstirring under ice-cooling for 1 hr. and at room temperature for 1 hr.,the precipitated solid was filtered off. After concentration underreduced pressure, ethyl acetate (50 mL) was added, and the mixture waswashed with an ice-cooled aqueous sodium hydrogen carbonate solution (50mL) and saturated brine (50 mL), and dried over anhydrous magnesiumsulfate. The layer was concentrated under reduced pressure, and theresidue was dissolved in tetrahydrofuran (20 mL).(R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g), triethylamine (0.63 mL) and 4-dimethylaminopyridine (0.037 g)were added, and the mixture was stirred at 60° C. overnight. Afterconcentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture wasextracted with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (50 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=1:1, then ethyl acetate, then methanol:ethylacetate=1:19) to give the title compound (0.70 g) as a yellow amorphoussolid.

¹H NMR(CDCl₃): 1.70-1.86 (2H, m), 1.90-2.04 (2H, m), 2.23 (3H, s), 2.28(3H, s), 2.10-2.35 (2H, m), 2.60-2.72 (2H, m), 3.08 (3H, bs), 3.40-4.20(2H, br), 4.39 (2H, q, J=7.9 Hz), 4.44 (2H, m), 4.60-4.74 (1H, m),4.80-5.15 (2H, br), 6.65 (1H, d, J=5.9 Hz), 7.35-7.52 (3H, m), 7.84 (1H,d, J=7.5 Hz), 8.35 (1H, d, J=5.9 Hz).

Synthetic Example 642-[[4-(Aminocarbonyl)phenyl][[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethylacetate

To a solution (5 mL) of bis(trichloromethyl)carbonate (0.12 g) intetrahydrofuran was dropwise added a solution (5 mL) of2-[[4-(aminocarbonyl)phenyl]amino]ethyl acetate (0.22 g) obtained inReference Example 55 and triethylamine (0.17 mL) in tetrahydrofuranunder ice-cooling, and the mixture was stirred at room temperature for30 min. Water (20 mL) was added, and the mixture was extracted withethyl acetate (30 mL). The ethyl acetate layer was washed with saturatedbrine (20 mL) and dried over anhydrous magnesium sulfate. Afterconcentration under reduced pressure, the residue was dissolved intetrahydrofuran (10 mL).2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole(0.37 g), triethylamine (0.28 mL) and 4-dimethylaminopyridine (0.012 g)were added, and the mixture was stirred at 60° C. for 1 hr. Afterconcentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (20 mL) was added to the residue, and the mixture wasextracted with ethyl acetate (30 mL). The ethyl acetate layer was washedwith saturated brine (20 mL) and dried over anhydrous magnesium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=3:7, then 5:5, then 8:2) to give the title compound (0.34g) as a pale-yellow amorphous solid.

¹H-NMR(CDCl₃): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H,q, J=7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J=5.9 Hz), 7.26-7.40 (3H,m), 7.47 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.65-7.74 (1H, m),8.38 (1H, d, J=5.9 Hz).

Synthetic Example 65 (−)-Ethyl2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethylcarbonate

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridinesynthesized according to the method described in JP-A-63-146882 wassubjected to preparative HPLC for optical resolution to give a (−)enantiomeric form (0.10 g) thereof. To a solution (5 mL) of this form intetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethylcarbonate (0.081 g) obtained in Reference Example 34, triethylamine(0.080 mL) and 4-dimethylaminopyridine (0.007 g) and the mixture wasstirred at 50° C. for 18 hrs. After concentration under reducedpressure, water (30 mL) was added to the residue and the mixture wasextracted with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (30 mL) and dried over anhydrous sodium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=2:1) to give the title compound (0.053 g) as a colorlessoil.

¹H-NMR(CDCl₃): 1.30 (3H, t, J=7.1 Hz), 2.24 (6H, s), 3.15, 3.32 (total3H, s), 3.73 (3H, s), 3.90-4.55 (9H, m), 4.85 (1H, d, J=13.2 Hz), 4.97(1H, d, J=13.2 Hz), 6.80 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=8.8 Hz), 8.23(1H, s).

Synthetic Example 66 (+)-Ethyl2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethylcarbonate

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridinesynthesized according to the method described in JP-A-63-146882 wassubjected to preparative HPLC for optical resolution to give a (+)enantiomeric form (0.10 g) thereof. To a solution (5 mL) of this form intetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethylcarbonate (0.081 g) obtained in Reference Example 34, triethylamine(0.080 mL) and 4-dimethylaminopyridine (0.007 g) and the mixture wasstirred at 50° C. for 18 hrs. After concentration under reducedpressure, water (30 mL) was added to the residue and the mixture wasextracted with ethyl acetate (50 mL). The ethyl acetate layer was washedwith saturated brine (30 mL) and dried over anhydrous sodium sulfate.After concentration under reduced pressure, the residue was purified bybasic silica gel column chromatography (eluted with ethylacetate:hexane=2:1) to give a 2:1 mixture (0.115 g) of the titlecompound and (+)-ethyl2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridin-1-yl]carbonyl](methyl)amino]ethylcarbonate as a colorless oil.

¹H-NMR(CDCl₃): 1.20-1.38 (3H, m), 2.24 (6H, s), 3.08, 3.15, 3.33 (total3H, s), 3.73 (3H, s), 3.88-4.55 (9H, m), 4.78-5.05 (2H, m), 6.80, 6.86(1H, d, J=8.8 Hz), 7.76, 7.96 (1H, d, J=8.8 Hz), 8.21, 8.22 (total 1H,s).

Example 1

Among the components described below, 247.7 g of lansoprazole R-isomer(hereinafter, referred to as ‘Compound A’), 184.6 g of magnesiumcarbonate, 492.2 g of purified sucrose, 299.9 g of corn starch and 329.6g of low substituted hydroxypropyl cellulose were mixed well to obtain adusting powder. 880 g of sucrose starch spheres (trade name:Nonpareil-101, produced by Freund Industrial Co., Ltd.) were charged ina centrifugal fluid-bed granulator (CF-360, manufactured by FreundIndustrial Co., Ltd.) and the above dusting powder was coated on thesucrose.starch spheres while spraying a hydroxypropyl cellulose solution(2 w/w %), thereby producing spherical granules. The spherical granuleswere dried at 40° C. for 16 hrs under vacuum and passed through a roundsieve to give granules of 710 μm-1400 μm.

Composition in 300.0 mg of the Granules

sucrose.starch spheres 110.0 mg  Compound A 30.0 mg magnesium carbonate22.4 mg purified sucrose 59.8 mg corn starch 36.4 mg low substitutedhydroxypropyl cellulose 40.0 mg hydroxypropyl cellulose  1.4 mg total300.0 mg 

Example 2

25 g of Macrogol 6000 and 10 g of Polysorbate 80 were dissolved in 1206g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7g of methacrylic acid copolymer LD (260 g as solid content) weredispersed into the resulting solution to obtain an enteric coatingsolution. The granules obtained in Example 1 were coated with the aboveenteric coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 45° C., rotor revolution speed: 200rpm, coating solution spray rate: 3.8 g/min. and spray air pressure: 1.0kg/cm², followed by drying as it was and passing through a round sieveto give enteric-coated granules of 710 μm-1400 μm having followingcomposition. The obtained spherical granules were dried at 40° C. for 16hrs under vacuum.

Composition in 369.2 mg of the Enteric-Coated Granules

granules of Example 1 300.0 mg methacrylic acid copolymer LD 148.7 mg(44.6 mg as solid content) talc 13.8 mg Macrogol 6000 4.4 mg titaniumoxide 4.4 mg Polysorbate 80 2.0 mg total 369.2 mg

Example 3

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the enteric-coated granules obtained in Example 2 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 605.5 mg of the Controlled Release Granules

enteric-coated granules of Example 2 369.2 mg methacrylic acid copolymerS 110.8 mg methacrylic acid copolymer L  36.9 mg talc  73.8 mg triethylcitrate  14.8 mg total 605.5 mg

Example 4

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain coatingsolution. 100 g of the enteric-coated granules obtained in Example 2 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 605.5 mg of the Controlled Release Granules

enteric-coated granules of Example 2 369.2 mg methacrylic acid copolymerS 73.85 mg methacrylic acid copolymer L 73.85 mg talc  73.8 mg triethylcitrate  14.8 mg total 605.5 mg

Example 5

104 mg of enteric-coated granules obtained in Example 2 and 500 mg ofcontrolled release granules obtained in Example 3 were mixed and thereto205 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, producedby Dow Chemical Co., Ltd.) was added to obtain a mixture. Two geratincapsules #0 were filled with the resulting mixture to obtain a capsule.

Example 6

104 mg of enteric-coated granules obtained in Example 2 and 500 mg ofcontrolled release granules obtained in Example 4 were mixed and thereto205 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, producedby Dow Chemical Co., Ltd.) was added to obtain a mixture. Two geratincapsules #0 were filled with the resulting mixture to obtain a capsule.

Example 7

300 g of Compound A, 105 g of magnesium carbonate, 195 g of purifiedsucrose and 75 g of low substituted hydroxypropyl cellulose were mixedwell to obtain a dusting powder for active ingredient layer. 75 g ofpurified sucrose, 48.8 g of titanium oxide and 18.8 g of low substitutedhydroxypropyl cellulose were mixed well to obtain a dusting powder forintermediate layer. 375 g of sucrose.starch spheres (trade name:Nonpareil-101, produced by Freund Industrial Co., Ltd.) were charged ina centrifugal fluid-bed granulator (CF-360, manufactured by FreundIndustrial Co., Ltd.) and the sucrose.starch spheres were coated withthe above dusting powder for active ingredient layer while spraying ahydroxypropyl cellulose solution (2 w/w %), thereby producing sphericalgranules. Then, the resulting spherical granules were coated with theabove dusting powder for intermediate layer while spraying ahydroxypropyl cellulose solution (2 w/w %) to obtain spherical granules.The obtained spherical granules were dried at 40° C. for 16 hrs undervacuum and passed through a round sieve to give granules of 710 μm-1400μm.

Composition in 120.0 mg of the Granules

sucrose.starch spheres 37.5 mg hydroxypropyl cellulose 0.75 mg dustingpowder for active ingredient layer Compound A 30.0 mg magnesiumcarbonate 10.5 mg purified sucrose 19.5 mg low substituted hydroxypropylcellulose  7.5 mg dusting powder for intermediate layer purified sucrose 7.5 mg low substituted hydroxypropyl cellulose 1.875 mg  titanium oxide4.875 mg  total 120.0 mg 

Example 8

25 g of Macrogol 6000 and 10 g of Polysorbate 80 were dissolved in 1206g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7g of methacrylic acid copolymer LD (260 g as solid content) weredispersed into the resulting solution to obtain an enteric coatingsolution. The granules obtained in Example 7 were coated with the aboveenteric coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 45° C., rotor revolution speed: 200rpm, coating solution spray rate: 3.8 g/min. and spray air pressure: 1.0kg/cm², followed by drying as it was and passing through a round sieveto give enteric-coated granules of 710 μm-1400 μm having the followingcomposition. The obtained spherical granules were dried at 40° C. for 16hrs under vacuum.

Composition in 149.86 mg of the Enteric-Coated Granules

granules of Example 7 120.00 mg methacrylic acid copolymer LD 65 mg(19.5 mg as solid content) talc 5.85 mg Macrogol 6000 1.88 mg titaniumoxide 1.88 mg Polysorbate 80 0.75 mg total 149.86 mg

Example 9

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the enteric-coated granules obtained in Example 8 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with a release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 245.86 mg of the Controlled Release Granules

enteric-coated granules of Example 8 149.86 mg  methacrylic acidcopolymer S 45.00 mg methacrylic acid copolymer L 15.00 mg talc 30.00 mgtriethyl citrate  6.00 mg total 245.86 mg 

Example 10

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the enteric-coated granules obtained in Example 8 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with a release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 245.86 mg of the Controlled Release Granules

enteric-coated granules of Example 8 149.86 mg methacrylic acidcopolymer S  30.0 mg methacrylic acid copolymer L  30.0 mg talc  30.0 mgtriethyl citrate   6.0 mg total 245.86 mg

Example 11

35.5 mg of enteric-coated granules obtained in Example 8 and 175 mg ofcontrolled release granules obtained in Example 9 were mixed and thereto70.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 12

35.5 mg of enteric-coated granules obtained in Example 8 and 175 mg ofcontrolled release granules obtained in Example 10 were mixed andthereto 70.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Experiment Example 1

A capsule obtained in Example 5 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 186 ng/mL, 132 ng/mL, 107 ng/mL, 303 ng/mL, 355ng/mL, 216 ng/mL and 113 ng/mL, respectively.

Experiment Example 2

A capsule obtained in Example 6 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 192 ng/mL, 137 ng/mL, 473 ng/mL, 478 ng/mL, 364ng/mL, 257 ng/mL and 28 ng/mL, respectively.

Experiment Example 3

A capsule obtained in Example 11 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 308 ng/mL, 245 ng/mL, 323 ng/mL, 81 ng/mL, 39 ng/mL,26 ng/mL and 0 ng/mL, respectively.

Experiment Example 4

A capsule obtained in Example 12 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 160 ng/mL, 319 ng/mL, 631 ng/mL, 371 ng/mL, 230ng/mL, 144 ng/mL and 25 ng/mL, respectively.

Example 13

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate, were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the enteric-coated granules obtained in Example 8 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with a release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 221.86 mg of the Controlled Release Granules

enteric-coated granules of Example 8 149.86 mg methacrylic acidcopolymer S  33.75 mg methacrylic acid copolymer L  11.25 mg talc  22.5mg triethyl citrate   4.5 mg total 221.86 mg

Example 14

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the enteric-coated granules obtained in Example 8 wascoated with the above coating solution using an agitation fluidized bedgranulator (SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.)under the condition of inlet air temperature: 30° C., rotor revolutionspeed: 150 rpm, coating solution spray rate: 3.3 g/min. and spray airpressure: 1.0 kg/cm² to give controlled release granules having thefollowing composition which is coated with a release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1400 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 221.86 mg of the Controlled Release Granules

enteric-coated granules of Example 8 149.86 mg methacrylic acidcopolymer S  22.5 mg methacrylic acid copolymer L  22.5 mg talc  22.5 mgtriethyl citrate   4.5 mg total 221.86 mg

Example 15

35.5 mg of enteric-coated granules obtained in Example 8 and 168 mg ofcontrolled release granules obtained in Example 13 were mixed andthereto 68.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 16

35.5 mg of enteric-coated granules obtained in Example 8 and 168 mg ofcontrolled release granules obtained in Example 14 were mixed andthereto 68.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 17

35.5 mg of enteric-coated granules obtained in Example 8 and 168 mg ofcontrolled release granules obtained in Example 13 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

Example 18

35.5 mg of enteric-coated granules obtained in Example 8 and 168 mg ofcontrolled release granules obtained in Example 14 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

Experiment Example 5

A capsule obtained in Example 14 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 403 ng/mL, 687 ng/mL, 803 ng/mL, 463 ng/mL, 329ng/mL, 217 ng/mL and 65 ng/mL, respectively.

Example 19

100 g of the granules obtained in Example 1 was charged in a centrifugalfluid-bed granulator (CF-mini, manufactured by Freund Industrial Co.,Ltd.) and Ac-Di-Sol that is a disintegrant were coated on the granulesby a ratio of 32 w/w % based on the granules while spraying a solutionof hydroxypropyl cellulose dissolved in isopropyl alcohol (8 w/w %),thereby producing spherical granules. The spherical granules were driedat 40° C. for 16 hrs under vacuum and passed through a round sieve togive granules of 1400 μm or less.

Example 20

24 g of aminoalkyl methacrylate copolymer RS was dissolved in acetone(120 g) and isopropyl alcohol (288 g), and 48 g of talc was dispersedinto the resulting solution to obtain a coating solution. 100 g of thegranules obtained in Example 19 was coated with the above coatingsolution using an agitation fluidized bed granulator (SPIR-A-FLOW,manufactured by Freund Industrial Co., Ltd.) under the condition ofinlet air temperature: 30° C., rotor revolution speed: 150 rpm, coatingsolution spray rate: 3.1 g/min. and spray air pressure: 1.0 kg/cm² togive controlled release granules having the following composition. Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 710 μm-1700 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum.

Composition in 130.0 mg of the Controlled Release Granules

granules of Example 19 100 mg aminoalkyl methacrylate copolymer RS 10.0mg talc 20.0 mg total 130.0 mg 

Example 21

104 mg of enteric-coated granules obtained in Example 2 and 420 mg ofcontrolled release granules obtained in Example 20 were mixed andthereto 175 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Twogelatin capsules #0 were filled with the resulting mixture to obtain acapsule (correspond to 30 mg of Compound A).

Example 22

104 mg of enteric-coated granules obtained in Example 2 and 420 mg ofcontrolled release granules obtained in Example 20 were mixed and theresulting mixture was filled in two gelatin capsules #0 to give acapsule (correspond to 30 mg of Compound A).

Experiment Example 6

A capsule obtained in Example 21 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 657 ng/mL, 406 ng/mL, 223 ng/mL, 504 ng/mL, 399ng/mL, 228 ng/mL and 50 ng/mL, respectively.

Example 23

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the granules obtained in Example 19 was coated withthe above coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 30° C., rotor revolution speed: 150rpm, coating solution spray rate: 3.3 g/min. and spray air pressure: 1.0kg/cm² to give controlled release granules having the followingcomposition. The resulting spherical granules were passed through around sieve to give controlled release granules of 710 μm-1700 μm. Thenthe obtained spherical granules were dried at 40° C. for 16 hrs undervacuum.

Composition in 164.0 mg of the Controlled Release Granules

granules of Example 19  100 mg methacrylic acid copolymer S 30.0 mgmethacrylic acid copolymer L 10.0 mg talc 20.0 mg triethyl citrate  4.0mg total 164.0 mg 

Example 24

104 mg of enteric-coated granules obtained in Example 2 and 614 mg ofcontrolled release granules obtained in Example 23 were mixed andthereto 239 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Twogelatin capsules #0 were filled with the resulting mixture to obtain acapsule (correspond to 30 mg of Compound A).

Example 25

104 mg of enteric-coated granules obtained in Example 2 and 614 mg ofcontrolled release granules obtained in Example 23 were mixed and theresulting mixture was filled in two gelatin capsules #0 to obtain acapsule (correspond to 30 mg of Compound A).

Experiment Example 7

A capsule obtained in Example 24 was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 106 ng/mL, 135 ng/mL, 639 ng/mL, 129 ng/mL, 49 ng/mL,16 ng/mL and 0 ng/mL, respectively.

Comparison Example 1

One gelatin capsule #0 obtained in Example 2, which was filled with 414mg of enteric-coated granules, was administered orally with 30 ml ofwater to a fasting beagle dog. Each plasma concentration of Compound Aat 1 hr, 2 hrs, 4 hrs, 6 hrs, 7 hrs, 8 hrs and 10 hrs afteradministration was 2,068 ng/mL, 689 ng/mL, 70 ng/mL, 0 ng/mL, 0 ng/mL, 0ng/mL and 0 ng/mL, respectively.

Example 26

150 g of Compound A, 50 g of magnesium carbonate, 25 g of lowsubstituted hydroxypropyl cellulose and 25 g of hydroxypropyl cellulosewere suspended in 1420 g of purified water to obtain a sprayingsolution. 200 g of crystalline cellulose (sphere) was charged in anagitation fluidized bed granulator (SPIR-A-FLOW, manufactured by FreundIndustrial Co., Ltd.) and was sprayed with the above spraying solutionunder the condition of inlet air temperature: 62° C., rotor revolutionspeed: 300 rpm, coating solution spray rate: 10 g/min. and spray airpressure: 1.0 kg/cm² to give spherical granules having the followingcomposition. The resulting spherical granules were dried at 40° C. for16 hrs under vacuum and passed through a round sieve to give controlledrelease granules of 500 μm-1400 μm.

Composition in 41.24 mg of the Granules

crystalline cellulose (sphere) 22.5 mg Compound A 11.25 mg  magnesiumcarbonate 3.75 mg low substituted hydroxypropyl cellulose 10.0 mghydroxypropyl cellulose 1.87 mg total 41.24 mg 

Example 27

90 g of Compound A, 31.5 g of magnesium carbonate, 58.5 g of purifiedsucrose and 22.5 g of low substituted hydroxypropyl cellulose were mixedwell to obtain a dusting powder of active ingredient layer. 110 g of thegranules obtained in Example 26 was charged in a centrifugal fluid-bedgranulator (CF-mini, manufactured by Freund Industrial Co., Ltd.) andwas coated with the above dusting powder of active ingredient layerwhile spraying a hydroxypropyl cellulose solution (2 w/w %), therebyproducing spherical granules having the following composition. Theobtained spherical granules were dried at 40° C. for 16 hrs under vacuumand passed through a round sieve to give granules of 710 μm-1400 μm.

Composition in 118.03 mg of the Granules

granules of Example 26 41.25 mg Compound A 33.75 mg magnesium carbonate11.81 mg purified sucrose 21.94 mg low substituted hydroxypropylcellulose  8.44 mg hydroxypropyl cellulose  0.84 mg total 118.03 mg 

Example 28

The granules obtained in Example 27 were coated with a coating solutionfor intermediate layer using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.), and weredried intact to give granules having the following composition. Thecoating solution for intermediate layer was produced by dissolving 20.09g of hydroxypropyl methylcellulose 2910 in 361.55 g of purified waterand followed by dispersing 8.03 g of titanium oxide and 12.05 g of talcinto the obtained solution. The coating operation was carried out underthe condition of inlet air temperature: 62° C., rotor revolution speed:200 rpm, coating solution spray rate: 3.0 g/min. and spray air pressure:1.0 kg/cm². The resulting spherical granules were dried at 40° C. for 16hrs under vacuum and passed through a round sieve to give granules of710 μm-1400 μm.

Composition in 133.03 mg of the Granules Coated with an IntermediateLayer

granules of Example 27 118.03 mg   hydroxypropyl methylcellulose 29107.5 mg talc 4.5 mg titanium oxide 3.0 mg total 133.03 mg  

Example 29

25 g of Macrogol 6000 and 10 g of Polysorbate 80 were dissolved in 1206g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7g of methacrylic acid copolymer LD (260 g as solid content) weredispersed into the resulting solution to obtain an enteric coatingsolution. The granules obtained in Example 28 were coated with the aboveenteric coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 45° C., rotor revolution speed: 200rpm, coating solution spray rate: 3.8 g/min. and spray air pressure: 1.0kg/cm², followed by drying as it was and passing through a round sieveto give enteric-coated granules of 710 μm-1400 μm having the followingcomposition. The obtained spherical granules were dried at 40° C. for 16hrs under vacuum.

Composition in 165.18 mg of the Enteric-Coated Granules

granules of Example 28 133.03 mg  methacrylic acid copolymer LD   70 mg(21 mg as solid content) talc 6.30 mg Macrogol 6000 2.02 mg titaniumoxide 2.02 mg Polysorbate 80 0.81 mg total 165.18 mg 

Example 30

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the granules obtained in Example 28 was coated withthe above coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 30° C., rotor revolution speed: 100rpm, coating solution spray rate: 3.0 g/min. and spray air pressure: 1.0kg/cm² to give controlled release granules having the followingcomposition which is coated with a release-controlled coating-layerbeing soluble pH-dependently (releasing an active ingredient under thecircumstances of more than a certain pH value). The resulting sphericalgranules were passed through a round sieve to give controlled releasegranules of 1180 μm-1700 μm. Then the obtained spherical granules weredried at 40° C. for 16 hrs under vacuum.

Composition in 196.88 mg of the Controlled Release Granules

granules of Example 28 133.03 mg methacrylic acid copolymer S  29.93 mgmethacrylic acid copolymer L  9.98 mg talc  19.95 mg triethyl citrate 3.99 mg total 196.88 mg

Example 31

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the granules obtained in Example 28 was coated withthe above coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 30° C., rotor revolution speed: 100rpm, coating solution spray rate: 3.0 g/min. and spray air pressure: 1.0kg/cm² to give controlled release granules having the followingcomposition which is coated with a release-controlled coating-layerbeing soluble pH-dependently (releasing an active ingredient under thecircumstances of more than a certain pH value). The resulting sphericalgranules were passed through a round sieve to give controlled releasegranules of 1180 μm-1700 μm. Then the obtained spherical granules weredried at 40° C. for 16 hrs under vacuum.

Composition in 196.88 mg of the Controlled Release Granules

granules of Example 28 133.03 mg  methacrylic acid copolymer S 19.95 mgmethacrylic acid copolymer L 19.95 mg talc 19.95 mg triethyl citrate 3.99 mg total 196.88 mg 

Example 32

28 mg of enteric-coated granules obtained in Example 29 and 98.7 mg ofcontrolled release granules obtained in Example 30 were mixed andthereto 42.3 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 33

28 mg of enteric-coated granules obtained in Example 29 and 98.7 mg ofcontrolled release granules obtained in Example 31 were mixed andthereto 42.3 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 34

56 mg of enteric-coated granules obtained in Example 29 and 197.4 mg ofcontrolled release granules obtained in Example 30 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 35

84 mg of enteric-coated granules obtained in Example 29 and 296.1 mg ofcontrolled release granules obtained in Example 30 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 36

42 mg of enteric-coated granules obtained in Example 29 and 148.05 mg ofcontrolled release granules obtained in Example 30 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 45 mg of Compound A).

Example 37

48 g of methacrylic acid copolymer S and 4.8 g of triethyl citrate weredissolved in a mixed solution of purified water (69.12 g) and absoluteethanol (622.08 g), and 24 g of talc was dispersed into the resultingsolution to obtain a coating solution. 100 g of the granules obtained inExample 30 was coated with the above coating solution using an agitationfluidized bed granulator (SPIR-A-FLOW, manufactured by Freund IndustrialCo., Ltd.) under the condition of inlet air temperature: 30° C., rotorrevolution speed: 100 rpm, coating solution spray rate: 3.0 g/min. andspray air pressure: 1.0 kg/cm² to give controlled release granuleshaving the following composition which is coated with arelease-controlled coating-layer being soluble pH-dependently (releasingan active ingredient under the circumstances of more than a certain pHvalue). The resulting spherical granules were passed through a roundsieve to give controlled release granules of 1180 μm-1700 μm. Then theobtained spherical granules were dried at 40° C. for 16 hrs undervacuum.

Composition in 207.52 mg of the Controlled Release Granules

granules of Example 30 196.88 mg  methacrylic acid copolymer S 6.65 mgtalc 3.32 mg triethyl citrate 0.67 mg total 207.52 mg 

Example 38

48 g of methacrylic acid copolymer S and 4.8 g of triethyl citrate weredissolved in a mixed solution of purified water (69.12 g) and absoluteethanol (622.08 g), and 24 g of talc was dispersed into the resultingsolution to obtain a coating solution. 100 g of the granules obtained inExample 31 was coated with the above coating solution using an agitationfluidized bed granulator (SPIR-A-FLOW, manufactured by Freund IndustrialCo., Ltd.) under the condition of inlet air temperature: 30° C., rotorrevolution speed: 100 rpm, coating solution spray rate: 3.0 g/min. andspray air pressure: 1.0 kg/cm² to give controlled release granuleshaving the following composition which is coated with arelease-controlled coating-layer being soluble pH-dependently (releasingan active ingredient under the circumstances of more than a certain pHvalue). The resulting spherical granules were passed through a roundsieve to give controlled release granules of 1180 μm-1700 μm. Then theobtained spherical granules were dried at 40° C. for 16 hrs undervacuum.

Composition in 207.52 mg of the Controlled Release Granules

granules of Example 31 196.88 mg  methacrylic acid copolymer S 6.65 mgtalc 3.32 mg triethyl citrate 0.67 mg total 207.52 mg 

Example 39

28 mg of enteric-coated granules obtained in Example 29 and 103.8 mg ofcontrolled release granules obtained in Example 37 were mixed andthereto 43.9 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 40

28 mg of enteric-coated granules obtained in Example 29 and 103.8 mg ofcontrolled release granules obtained in Example 38 were mixed andthereto 43.9 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 41

56 mg of enteric-coated granules obtained in Example 29 and 207.5 mg ofcontrolled release granules obtained in Example 37 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 42

84 mg of enteric-coated granules obtained in Example 29 and 311.3 mg ofcontrolled release granules obtained in Example 37 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 43

42 mg of enteric-coated granules obtained in Example 29 and 155.6 mg ofcontrolled release granules obtained in Example 37 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 45 mg of Compound A).

Example 44

300 g of Compound A, 105 g of magnesium carbonate, 195 g of purifiedsucrose and 75 g of low substituted hydroxypropyl cellulose were mixedwell to obtain a dusting powder for active ingredient layer. 75 g ofpurified sucrose, 48.8 g of titanium oxide and 18.8 g of low substitutedhydroxypropyl cellulose were mixed well to obtain a dusting powder forintermediate layer. 375 g of sucrose.starch spherical granules (tradename: Nonpareil-101, produced by Freund Industrial Co., Ltd.) werecharged in a centrifugal fluid-bed granulator (CF-360, manufactured byFreund Industrial Co., Ltd.) and the sucrose.starch spheres were coatedwith the above dusting powder for active ingredient layer while sprayinga hydroxypropyl cellulose solution (2 w/w %), thereby producingspherical granules. The obtained spherical granules were dried at 40° C.for 16 hrs under vacuum and passed through a round sieve to givegranules of 710 μm-1400 μm.

Composition in 158.07 mg of the Granules

sucrose.starch spheres 56.25 mg hydroxypropyl cellulose  0.57 mg dustingpowder for active ingredient layer Compound A 45.00 mg magnesiumcarbonate 15.75 mg purified sucrose 29.25 mg low substitutedhydroxypropyl cellulose 11.25 mg total 158.07 mg 

Example 45

The granules obtained in Example 44 were coated with a coating solutionfor intermediate layer using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.), and weredried intact to give granules having the following composition. Thecoating solution for intermediate layer was produced by dissolving 20.09g of hydroxypropyl methylcellulose 2910 in 361.55 g of purified waterand followed by dispersing 8.03 g of titanium oxide and 12.05 g of talcinto the obtained solution. The coating operation was carried out underthe condition of inlet air temperature: 62° C., rotor revolution speed:200 rpm, coating solution spray rate: 3.0 g/min. and spray air pressure:1.0 kg/cm². The resulting spherical granules were dried at 40° C. for 16hrs under vacuum and passed through a round sieve to give granules of710 μm-1400 μm.

Composition in 188.07 mg of the Granules Coated with an IntermediateLayer

granules of Example 44 158.07 mg hydroxypropyl methylcellulose 2910 15.00 mg talc  9.00 mg titanium oxide  6.00 mg total 188.07 mg

Example 46

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymerL and 4.8 g of triethyl citrate were dissolved in a mixed solution ofpurified water (69.12 g) and absolute ethanol (622.08 g), and 24 g oftalc was dispersed into the resulting solution to obtain a coatingsolution. 100 g of the granules obtained in Example 45 was coated withthe above coating solution using an agitation fluidized bed granulator(SPIR-A-FLOW, manufactured by Freund Industrial Co., Ltd.) under thecondition of inlet air temperature: 30° C., rotor revolution speed: 100rpm, coating solution spray rate: 3.0 g/min. and spray air pressure: 1.0kg/cm² to give controlled release granules having the followingcomposition which is coated with a release-controlled coating-layerbeing soluble pH-dependently (releasing an active ingredient under thecircumstances of more than a certain pH value). The resulting sphericalgranules were passed through a round sieve to give controlled releasegranules of 1180 μm-1700 μm. Then the obtained spherical granules weredried at 40° C. for 16 hrs under vacuum.

Composition in 278.35 mg of the Controlled Release Granules

granules of Example 45 188.07 mg  methacrylic acid copolymer S 42.32 mgmethacrylic acid copolymer L 14.11 mg talc 28.21 mg triethyl citrate 5.64 mg total 278.35 mg 

Example 47

35.5 mg of enteric-coated granules obtained in Example 8 and 139.2 mg ofcontrolled release granules obtained in Example 46 were mixed andthereto 58.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant,produced by Dow Chemical Co., Ltd.) was added to obtain a mixture. Onecapsule #1 was filled with the resulting mixture to obtain a capsule(correspond to 30 mg of Compound A).

Example 48

71 mg of enteric-coated granules obtained in Example 8 and 278.35 mg ofcontrolled release granules obtained in Example 46 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 60 mg of Compound A).

Example 49

106.5 mg of enteric-coated granules obtained in Example 8 and 417.5 mgof controlled release granules obtained in Example 46 were mixed and theresulting mixture was filled in two capsules #2 to give a capsule(correspond to 90 mg of Compound A).

Example 50

53.3 mg of enteric-coated granules obtained in Example 8 and 208.8 mg ofcontrolled release granules obtained in Example 46 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 45 mg of Compound A).

Example 51

824.4 g of Compound A, 303.2 g of magnesium carbonate, 1062 g ofpurified sucrose and 228.2 g of low substituted hydroxypropyl cellulosewere mixed well to obtain a dusting powder for active ingredient layer.722.4 g of sucrose.starch spheres (trade name: Nonpareil-101, producedby Freund Industrial Co., Ltd.) were charged in a centrifugal fluid-bedgranulator (CF-360, manufactured by Freund Industrial Co., Ltd.) and thesucrose.starch spheres were coated with the above dusting powder foractive ingredient layer while spraying a hydroxypropyl cellulosesolution (2 w/w %), thereby producing spherical granules. The obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum andpassed through a round sieve to give granules of 710 μm-1400 μm.

Composition in 86.67 mg of the Granules

sucrose.starch spheres 20.64 mg hydroxypropyl cellulose  0.24 mg dustingpowder for active ingredient layer Compound A 22.50 mg magnesiumcarbonate  8.25 mg purified sucrose 28.83 mg low substitutedhydroxypropyl cellulose  6.21 mg total 86.67 mg

Example 52

The granules obtained in Example 51 were coated with a coating solutionfor intermediate layer using a fluid-bed fluidized bed coating machine(MP-10, manufactured by Powrex Co., Ltd.), and were dried intact to givegranules having the following composition. The coating solution forintermediate layer was produced by dissolving 270.0 g of hydroxypropylmethylcellulose 2910 in 4874 g of purified water and followed bydispersing 163.5 g of titanium oxide and 108 g of talc into the obtainedsolution. The coating operation was carried out under the condition ofinlet air temperature: 67° C., inlet air volume: 1.5 m³/min., coatingsolution spray rate: 12.0 g/min., spray air pressure: 0.28 MPa and sprayair volume: 90 Nl/hr. The resulting spherical granules were dried at 40°C. for 16 hrs under vacuum and passed through a round sieve to givegranules of 710 μm-1400 μm.

Composition in 97.50 mg of the Granules Coated with an IntermediateLayer

granules of Example 51 86.67 mg  hydroxypropyl methylcellulose 2910 5.40mg talc 2.16 mg titanium oxide 3.27 mg total 97.50 mg 

Example 53

57.60 g of Macrogol 6000 and 26.40 g of Polysorbate 80 were dissolved in2724 g of purified water, and 174 g of talc, 57.6 g of titanium oxideand 19323 g of methacrylic acid copolymer LD (579.6 g as solid content)were dispersed into the resulting solution to obtain an enteric coatingsolution. The granules obtained in Example 52 were coated with the aboveenteric coating solution using an agitation fluidized bed granulator(MP-10, manufactured by Powrex Co., Ltd.) under the condition of inletair temperature: 65° C., inlet air volume: 1.5 m³/min., coating solutionspray rate: 15.0 g/min. and spray air pressure: 0.30 MPa, and spray airvolume: 90 Nl/hr. The resulting granules were dried as it was and passedthrough a round sieve to give enteric-coated granules of 710 μm-1400 μmhaving the following composition. The obtained spherical granules weredried at 40° C. for 16 hrs under vacuum, and to 1918 g of the granuleswere added 0.96 g of talc and 0.96 g of aerosil to give enteric-coatedgranules.

Composition in 120.0 mg of the Enteric-Coated Granules

granules of Example 52 97.5 mg methacrylic acid copolymer LD 48.3 mg(14.49 mg as solid content) talc 4.35 mg Macrogol 6000 1.44 mg titaniumoxide 1.44 mg Polysorbate 80 0.66 mg talc 0.06 mg aerosil 0.06 mg total120.0 mg 

Example 54

1131 g of Compound A, 303.2 g of magnesium carbonate, 750.1 g ofpurified sucrose and 226.8 g of low substituted hydroxypropyl cellulosewere mixed well to obtain a dusting powder for active ingredient layer.720.0 g of sucrose.starch spheres (trade name: Nonpareil-101, producedby Freund Industrial Co., Ltd.) were charged in a centrifugal fluid-bedgranulator (CF-360, manufactured by Freund Industrial Co., Ltd.) and thesucrose.starch spheres were coated with the above dusting powder foractive ingredient layer while spraying a hydroxypropyl cellulosesolution (2 w/w %), thereby producing spherical granules. The obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum andpassed through a round sieve to give granules of 710 μm-1400 μm.

Composition in 189.0 mg of the Granules

sucrose.starch spheres 45.0 mg hydroxypropyl cellulose 0.54 mg dustingpowder for active ingredient layer Compound A 67.5 mg magnesiumcarbonate 18.0 mg purified sucrose 44.46 mg  low substitutedhydroxypropyl cellulose 13.5 mg total 189.0 mg 

Example 55

The granules obtained in Example 54 were coated with a coating solutionfor intermediate layer using a fluid-bed fluidized bed coating machine(MP-10, manufactured by Powrex Co., Ltd.), and were dried intact to givegranules having the following composition. The coating solution forintermediate layer was produced by dissolving 236.4 g of hydroxypropylmethylcellulose 2910 in 4255 g of purified water and followed bydispersing 141.6 g of titanium oxide and 94.8 g of talc into theobtained solution. The coating operation was carried out under thecondition of inlet air temperature: 65° C., inlet air volume: 1.5m³/min., coating solution spray rate: 12.0 g/min., spray air pressure:0.26 MPa and spray air volume: 90 Nl/hr. The resulting sphericalgranules were dried at 40° C. for 16 hrs under vacuum and passed througha round sieve to give granules of 710 μm-1400 μm.

Composition in 212.64 mg of the Granules Coated with an IntermediateLayer

granules of Example 54 189.0 mg hydroxypropyl methylcellulose 2910 11.82mg talc  4.74 mg titanium oxide  7.08 mg total 212.64 mg 

Example 56

382.8 g of methacrylic acid copolymer S, 127.7 g of methacrylic acidcopolymer L and 50.88 g of triethyl citrate were dissolved in a mixedsolution of purified water (734.8 g) and absolute ethanol (6614 g), and255.1 g of talc was dispersed into the resulting solution to obtain acoating solution. The granules obtained in Example 55 was coated withthe above coating solution using an agitation fluidized bed granulator(MP-10, manufactured by Powrex Co., Ltd.) under the condition of inletair temperature: 65° C., inlet air volume: 1.5 m³/min., coating solutionspray rate: 15.0 g/min., spray air pressure: 0.30 MPa and spray airvolume: 90 Nl/hr to give controlled release granules having thefollowing composition which is coated with a release-controlledcoating-layer being soluble pH-dependently (releasing an activeingredient under the circumstances of more than a certain pH value). Theresulting spherical granules were passed through a round sieve to givecontrolled release granules of 1180 μm-1700 μm. Then the obtainedspherical granules were dried at 40° C. for 16 hrs under vacuum, and to1101 g of the granules were added 0.525 g of talc and 0.525 g of aerosilto give enteric-coated granules.

Composition in 315.0 mg of the Controlled Release Granules

granules of Example 55 212.64 mg  methacrylic acid copolymer S 47.85 mgmethacrylic acid copolymer L 15.96 mg talc 31.89 mg triethyl citrate 6.36 mg talc  0.15 mg aerosil  0.15 mg total 315.0 mg

Example 57

120 mg of enteric-coated granules obtained in Example 53 and 315 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 58

80 mg of enteric-coated granules obtained in Example 53 and 210 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 59

40 mg of enteric-coated granules obtained in Example 53 and 105 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

Example 60

240 mg of enteric-coated granules obtained in Example 53 and 210 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 61

160 mg of enteric-coated granules obtained in Example 53 and 280 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 62

192 mg of enteric-coated granules obtained in Example 53 and 252 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 90 mg of Compound A).

Example 63

160 mg of enteric-coated granules obtained in Example 53 and 210 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 75 mg of Compound A).

Example 64

100 mg of enteric-coated granules obtained in Example 53 and 262.5 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 75 mg of Compound A).

Example 65

133.3 mg of enteric-coated granules obtained in Example 53 and 233.3 mgof controlled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 75 mg of Compound A).

Example 66

200 mg of enteric-coated granules obtained in Example 53 and 175 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #1 to give a capsule(correspond to 75 mg of Compound A).

Example 67

106.7 mg of enteric-coated granules obtained in Example 53 and 186.7 mgof controlled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 68

128 mg of enteric-coated granules obtained in Example 53 and 168 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 69

160 mg of enteric-coated granules obtained in Example 53 and 140 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 60 mg of Compound A).

Example 70

60 mg of enteric-coated granules obtained in Example 53 and 157.5 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 45 mg of Compound A).

Example 71

120 mg of enteric-coated granules obtained in Example 53 and 105 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 45 mg of Compound A).

Example 72

80 mg of enteric-coated granules obtained in Example 53 and 140 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 45 mg of Compound A).

Example 73

96 mg of enteric-coated granules obtained in Example 53 and 126 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #2 to give a capsule(correspond to 45 mg of Compound A).

Example 74

53.3 mg of enteric-coated granules obtained in Example 53 and 93.3 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

Example 75

64 mg of enteric-coated granules obtained in Example 53 and 84 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

Example 76

80 mg of enteric-coated granules obtained in Example 53 and 70 mg ofcontrolled release granules obtained in Example 56 were mixed and theresulting mixture was filled in one capsule #3 to give a capsule(correspond to 30 mg of Compound A).

INDUSTRIAL APPLICABILITY

Since the controlled release preparation of the present invention canextend the therapeutic effective level by controlling the release ofactive ingredient over a long time, it can provide the effectiveness oftreatment with a low dose and the reduction of side effects caused bythe rise of blood level, as well as the reduction of administrationtimes.

The invention claimed is:
 1. A capsule comprising: composition (i)comprising a tablet, granule or fine granule in which a release of anactive ingredient is controlled; said tablet, granule or fine granulecomprising a core particle containing an imidazole compound representedby formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as the active ingredient, and a pH-dependentlysoluble release-controlled coating-layer which comprises one kind ofpolymeric substance or a mixture of two or more kinds of polymericsubstances having different release properties selected from the groupconsisting of hydroxypropylmethyl cellulose phthalate, cellulose acetatephthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylicacid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylicacid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate, polyvinyl acetate phthalate and shellac,wherein the active ingredient is released at an elution rate of 10% orless for 5 hours in a solution of pH 6.0, and 5% or less for one hourand 60% or more for 8 hours in a solution of pH 6.8, and composition(ii) comprising a tablet, granule or fine granule comprising a coreparticle containing the active ingredient and enteric coat, such thatthe active ingredient is released in the pH range of no less than 5.0 tono more than 6.0, wherein the composition (i) and the composition (ii)in the capsule individually contain a sufficient amount of the imidazolecompound represented by formula (I′) to raise a plasma level of theimidazole compound represented by formula (I′) in a mammal to whom thecapsule is administered to at least 100 ng/ml.
 2. The capsule accordingto claim 1, wherein the plasma level of at least 100 ng/ml in the mammalcontinues for at least 8 hours.
 3. The capsule according to claim 1,wherein the composition (i) and the composition (ii) in the capsuleindividually contain a sufficient amount of the imidazole compoundrepresented by formula (I′) to raise the plasma level in the mammal toat least 300 ng/ml.
 4. A capsule comprising: composition (i) comprisinga tablet, granule or fine granule in which a release of an activeingredient is controlled; said tablet, granule or fine granulecomprising a core particle containing an imidazole compound representedby formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as the active ingredient, and a pH-dependentlysoluble release-controlled coating-layer which comprises one kind ofpolymeric substance or a mixture of two or more kinds of polymericsubstances having different release properties, selected from the groupconsisting of hydroxypropylmethyl cellulose phthalate, cellulose acetatephthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylicacid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylicacid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate, polyvinyl acetate phthalate and shellac,wherein the active ingredient is released at an elution rate of 10% orless for 5 hours in a solution of pH 6.0, and 5% or less for one hourand 60% or more for 8 hours in a solution of pH 6.8, and composition(ii) comprising a tablet, granule or fine granule comprising a coreparticle containing the active ingredient and enteric coat, such thatthe active ingredient is released in the pH range of no less than 5.0 tono more than 6.0, wherein the imidazole compound represented by formula(I′) contained in the composition (i) and the composition (ii) in thecapsule is released from the capsule in a pulsatile manner, wherein theplasma level of the imidazole compound released from each of thecomposition (i) and the composition (ii) rises to at least 100 ng/ml ina mammal to whom the capsule is administered.
 5. The capsule accordingto claim 4, wherein a plasma level of the imidazole compound releasedfrom each of the compositions (i) and the composition (ii) rises to atleast 300 ng/ml in a mammal to whom the capsule is administered.
 6. Acapsule comprising: composition (i) comprising a tablet, granule or finegranule in which a release of an active ingredient is controlled; saidtablet, granule or fine granule comprising a core particle containing animidazole compound represented by formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as the active ingredient, and a pH-dependentlysoluble release-controlled coating-layer which comprises one kind ofpolymeric substance or a mixture of two or more kinds of polymericsubstances having different release properties selected from the groupconsisting of hydroxypropylmethyl cellulose phthalate, cellulose acetatephthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylicacid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylicacid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate, polyvinyl acetate phthalate and shellac,wherein the active ingredient is released at an elution rate of 10% orless for 5 hours in a solution ofpH 6.0, and 5% or less for one hour and60% or more for 8 hours in a solution of pH 6.8, and composition (ii)comprising a tablet, granule or fine granule comprising a core particlecontaining the active ingredient and enteric coat, such that the activeingredient is released in the pH range of no less than 5.0 to no morethan 6.0, wherein an amount of the imidazole compound represented byformula (I′) in the composition (i) is at least 50% more than an amountof the imidazole compound in the composition (ii), wherein thecomposition (i) and the composition (ii) in the capsule individuallycontain a sufficient amount of imidazole compound represented by formula(I′) to raise the plasma level of the imidazole compound represented byformula (I′) in a mammal to whom the capsule is administered to at least100 ng/ml.
 7. The capsule according to claim 6, wherein the amount ofthe imidazole compound contained in the composition (i) is at leasttwice the amount of the imidazole compound contained in the composition(ii).
 8. The capsule according to claim 6, wherein the amount of theimidazole compound contained in the composition (i) is at least threetimes the amount of the imidazole compound contained in the composition(ii).
 9. A capsule comprising: composition (i) comprising a tablet,granule or fine granule in which a release of an active ingredient iscontrolled; said tablet, granule or fine granule comprising a coreparticle containing an imidazole compound represented by formula (I′):

wherein ring C′ is an optionally substituted benzene ring or anoptionally substituted aromatic monocyclic heterocyclic ring, R⁰ is ahydrogen atom, an optionally substituted aralkyl group, acyl group oracyloxy group, R¹, R² and R³ are the same or different and are ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted alkoxy group or an optionally substituted amino group, and Yrepresents a nitrogen atom or CH; or a salt thereof or an opticallyactive isomer thereof as the active ingredient, and a pH-dependentlysoluble release-controlled coating-layer which comprises one kind ofpolymeric substance or a mixture of two or more kinds of polymericsubstances having different release properties selected from the groupconsisting of hydroxypropylmethyl cellulose phthalate, cellulose acetatephthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylicacid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylicacid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate, polyvinyl acetate phthalate and shellac,wherein the active ingredient is released at an elution rate of 10% orless for 5 hours in a solution of pH 6.0, and 5% or less for one hourand 60% or more for 8 hours in a solution of pH 6.8, and composition(ii) comprising a tablet, granule or fine granule comprising a coreparticle containing the active ingredient and enteric coat, such thatthe active ingredient is released in the pH range of no less than 5.0 tono more than 6.0, wherein a total amount of the imidazole compoundrepresented by formula (I′) in the composition (i) and the composition(ii) is between 5 mg and 150 mg, wherein the composition (i) and thecomposition (ii) in the capsule individually contain a sufficient amountof imidazole compound represented by formula (I′) to raise the plasmalevel of the imidazole compound represented by formula (I′) in a mammalto whom the capsule is administered to at least 100 ng/ml.
 10. Thecapsule according to claim 9, wherein the total amount of the imidazolecompound represented by formula (I′) in the composition (i) and thecomposition (ii) is between 30 mg and 90 mg.
 11. The capsule accordingto claim 4, wherein the capsule provides two plasma level peaks in amammal to whom the capsule is administered and a plasma level lower thanthe plasma level peaks is present between the two plasma level peaks.